分子医学所现有研究员的研究领域与经历介绍
一、Principal Investigator：肖瑞平（Rui-Ping Xiao）
Personal Synopsis
Rui-Ping (Ping) Xiao was trained as a cardiologist and
physiologist at Tong-Ji Medical University in Wuhan, China and
the Medical School at University of Maryland at Baltimore (UMAB),
where she earned her M.D. in
1984 and Ph.D. in 1995,
respectively. She joined the Laboratory of Cardiovascular Science,
National Institute of Aging, in 1990 as a postdoctoral fellow,
and later in 1996 became a tenure-track investigator and the head
of the Receptor Signaling Unit. In 2004, she was converted to
Senior Investigator at National Institute of Health, USA. She
is now a Senior Investigator and co-PI of the Laboratory of
Cellular Signaling Network at IMM, PKU.
Research Interest
The scope of
her research work covers three intertwined
programs: (I) -adrenergic receptor subtype signaling in
cardiovascular system; (II) Modulation of cardiac
excitation-contraction coupling by Ca/calmodulin-dependent
protein kinase II (CaMKII) in normal and failing hearts; and
(III) Identification and characterization of cardiovascular
disease-related genes.
Her main scientific focus has been
G-protein coupled receptor (GPCR) signaling in the cardiovascular
system. Using interdisciplinary approaches,
including physiological and pharmacological techniques in
conjunction with genetic manipulations (e.g. gene-targeted
animal models or adenoviral gene transfer systems), her
work revealed dual coupling of 2-adrenergic receptor (b2AR)
with two functionally opposite G-protein families, Gs and Gi
proteins. This counterintuitive finding was the first
demonstration that a given GPCR can couple to more than one class
of G-proteins in a physiological context such as in intact
cardiac myocytes.
Dr. Xiao’s research has demonstrated that the additional Gi
coupling creates a microscopic compartmentalization of the
concurrent Gs-cAMP signaling and, more importantly, dictates the
opposing outcomes of AR subtype stimulation with respect to
cardiac cell survival and apoptotic cell death.
Dr. Xiao envisioned and promoted the perception that 1AR and
2AR subtypes play distinctly different-even opposing-roles in
the context of heart failure. Specifically, while 1AR is widely
recognized as a "foe," 2AR might be a "friend" in need due to
its concurrent anti-apoptotic effect and contractile
support. This new perception of AR signal transduction has been
increasingly appreciated in the cardiovascular research
community and provides a novel rationale for new therapeutic
strategies, particularly a combination of 1AR blockade with 2AR
activation for improving the function of the failing heart.
Dr. Xiao’s research has not been limited to G protein-coupled
receptor signaling. She was also the first to characterize role
2+
of CaMKII in regulating cardiac L-type Ca currents and in the
control of cardiac pacemaker activity. Her recent in vivo and
in vitro studies have shown that activation of p38 MAPK exhibits
a potent inhibitory effect on cardiac contractility. In addition,
She has put considerable efforts to understand mechanisms
underlying cardiac aging and heart failur.
Human Genome Project has demonstrated that the family of G protein
coupled receptors (GPCRs) is the largest gene family in human
genome. The GPCR superfamily has also long been considered the
most important target in the pharmaceutical industry. Remarkably,
70% of today’s therapeutic agents used for the treatment of
cardiovascular diseases are targeted at GPCR signaling pathways.
Thus, one of Dr. Xiao’s major future directions will
be focused on identification and target validation of orphan
GPCRs . These studies will not only provide novel insights
into basic mechanisms of novel GPCRs actions, but also reveal
new rationales for ligand screens as well as clinical
applications.
Additionally, identification and
characterization of cardiovascular disease-related genes
is another new initiative of Dr. Xiao’s lab.
Selected Publuications
1.
Xiao, R.P., and Lakatta, E.G.:
1-adrenoceptor stimulation and
2-adrenoceptor stimulation differ in their effects on contraction, cytosolic
calcium, and calcium current in single rat ventricular cells. Circ. Res. 73:
286-300, 1993.
2.
Xiao, R.P., Spurgeon, H.A., O'Connor, F., and Lakatta, E.G.:
Age-associated changes in -adrenergic modulation on rat cardiac
excitation-contraction coupling. J. Clin. Invest. 94: 2051-2059, 1994.
3.
Xiao, R.P., Cheng, H., Lederer, W.J., Suzuki, T., and Lakatta, E.G.: Dual
regulation of Ca2+/calmodulin-dependent Kinase II activity by membrane
voltage and by calcium influx. Proc. Nat. Acad., Sci. USA 91: 9659-9663,
1994.
4.
Xiao, R.P., Hohl, C., Altschuld, R., Jones, L., Livingston, B., Ziman, B.,
Tantini, B., and Lakatta, E.G.: 2-adrenergic receptor-stimulated increase
in cAMP in rat heart cells is not coupled to changes in Ca2+ dynamics,
contractility, or phospholamban phosphorylation. J. Biol. Chem. 269:
19151-19156, 1994.
5.
Xiao, R.P., Ji, X., and Lakatta, E.G.: Functional coupling of the
2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes.
Mol. Pharmacol. 47: 322-329, 1995.
6.
Altschuld, R.A., Starling, R.C., Hamlin, R.L., Hensley, J., Castillo, L., Fertel,
R.H., Hohl, C.M., Robitaille, P.M., Jones, L.R., Xiao, R.P., and Lakatta,
E.G.: Response of failing canine and human heart cells to 2-adrenergic
stimulation. Circulation. 92: 1612-1618, 1995.
7.
Xiao, R.P., Pepe, S., Capogrossi, M.C., Spurgeon, H.A., and Lakatta, E.G.:
Opioid peptide receptor stimulation reverses -adrenergic effects in rat
heart cells. Am. J. Physiol. 272: H797-H805, 1997.
8.
Pepe, S., Xiao, R.P., Hohl, C., Altschuld, R., and Lakatta, E.G.: "Cross-talk"
between opioid peptide and -adrenergic receptor signaling in rat heart.
Circulation 95: 2122-2129, 1997.
9.
Xiao, R.P., Valdivia, H.H., Bogdanov, K., Valdivia, C., Lakatta, E.G., and
Cheng, H.: The Immunophilin FK506 binding protein (FKBP) modulates
Ca2+ release channel closure in rat heart cells. J. Physiol. 500: 331-342,
1997.
10. 18.
Zhou, Y.Y., Cheng, H., Bogdanov, K., Hohl, C., Altschuld, R.,
Lakatta, E.G., and Xiao R.P.: Localized cAMP-dependent pathway
mediates 2-adrenergic stimulation in rat ventricular myocytes. Am. J.
Physiol. 273: H1611-1618, 1997.
11. Xiao, R.P., Tomhave, E.D., Ji, X., Boluyt, M.O., Cheng, H., Lakatta, E.G.,
and Koch, W.J.: Age-associated reductions in cardiac 1- and
2-adrenoceptor responses without changes in inhibitory G proteins or
receptor kinases. J. Clin. Invest. 101: 1273-1282, 1998.
12. Xiao, R.P., Avdonin, P., Zhou, Y.Y., Cheng, H., Akhter, S.A., Eschenhagen,
T., Lefkowitz, R.J., Koch, W.J., and Lakatta, E.G.: Coupling of
2-adrenoceptor to Gi proteins and its physiological releavance in murine
cardiac myocytes.
Circ. Res. 84:43-52, 1999.
13. Kuschel, M., Bartel, S., Spurgeon, H.A., Zhou, Y.Y., Zhang, S.J., Krause, E.G., Lakatta,
E.G., and Xiao, R.P.: Canine cardiac 2-adrenergic signaling is localized to the
sarcolemma membrane. Circulation 99:2458-2465, 1999.
14. Kuschel, M., Zhou, Y.Y., Cheng, H., Zhang, S.J., Chen-Izu, Y., Lakatta, E.G.,
and Xiao, R.P.: Gi protein-mediated functional compartmentalization of
cardiac 2-adrnergic signaling. J. Biol. Chem. 274: 22048-22052, 1999.
15. Zhou, Y.Y., Cheng, H., Song, L.S., Lakatta, E.G., and Xiao, R.P.:
Differential regulation of cardiac L-type calcium channel current by
constitutively active and agonist-activated 2-adrenergic receptor signaling.
Mol. Parmacol. 56: 485？93, 1999.
16. Xiao, R.P., Cheng, H., Zhou, Y.Y., Kuschel, M., and Lakatta, E.G.: Recent
advances in cardiac -adrenergic receptor subtype signal transduction.
Circ. Res. 85:1092-1100, 1999 (Invited Review).
17. Zhou, Y.Y., Song, L.S., Lakatta, E.G., Xiao, R.P., and Cheng, H.:
Constitutive 2-adrenergic signaling enhances SR calcium to augment
contraction in mouse heart. J. Physiol. 521: 351-363, 1999.
18. Zhang, S.J., Cheng, H., Zhou, Y.Y., Wang, D.J., Zhu, W., Ziman, B.,
Spurgeon, H., Lefkowitz, R.J., Lakatta, E.G., Koch, W.J., and Xiao, R.P.:
Inhibition of spontaneous 2-adrenergic activation rescues 1-adrenergic
contractile response in cardiomyocytes overexpressing 2-adrenoceptor. J.
Biol. Chem. 275: 21773-21779, 2000.
19. Hagemann, D., Kuschel, M., Kuromochi, T., Zhu, W., Cheng, H., and Xiao,
R.P.: Frequency-encoding Thr17 phospholamban phosphorylation is
independent of Ser16 phosphorylation in cardiac myocytes. J. Biol. Chem.
275: 22532-22536, 2000.
20. Vinogradova, T.M., Zhou, Y.Y., Bogdanov, K.Y., Kuschel, M., Cheng, H.,
and Xiao, R.P.: Sinoatrial node pacemaker activity requires
Ca2+/calmodulin-dependent protein kinase II activation. Circ. Res. 87:
760-767, 2000.
21. Xiao, R.P.: Cell logic for dual coupling of a single class of receptors to Gs
and Gi proteins. Cric. Res. 87:635-637, 2000 (Editorial).
22. Zhou, Y.Y., Zhu, W., Zhang, S..J., Wang, D.J., Kobilka, B., Lakatta, E.G.,
Cheng, H., and Xiao, R.P.: Ligand-independent activation of 2- but not
1-adrenoceptor overexpressed in 1/2-adrenoceptor double knockout
mouse cardiomyocytes. Mol. Pharmacol. 58: 887-894, 2000.
23. Zheng, M., Zhang, S.J., Zhu, W., Ziman, B., Kobilka, B.K., and Xiao, R.P.:
adrenergic receptor-induced p38 MAPK activation is mediated by PKA rather
than by Gi or G( in adult mouse cardiomyocytes. J. Biol. Chem. 275:
40635-40640, 2000.
24. Zhu, W.Z., Zheng, M., Lefkowitz, R.J., Koch, W.J., Kobilka, B., and Xiao,
R.P.: Dual modulation of cardiac cell survival and cell death by 2-adrenergic
signaling in adult mouse heart cells. Proc. Nat. Acad., Sci. USA 98:
1607-1612, 2001.
25. Xiao, R.P.: β-adrenergic signaling in the heart: Dual coupling of the
β2-adrenergic receptor to Gs and Gi proteins. Science’s STKE. 16:RE15, 2001
(invited Review).
26. Liao, P., Wang, S.Q., Zheng, M., Zheng, M.Z., Cheng, H., Wang, Y., and
Xiao, R.P.: p38 mitogen activated protein kinase mediates negative
inotropic effect in cardiac myocytes. Circ. Res. 90:190-196, 2002.
27. Jo, S.H., Leblais, V., Crow, M.T., and Xiao, R.P.: Phosphatidylinositol
3-kinase functionally compartmentalizes the concurrent Gs signaling during
2-adrenergic stimulation. Circ. Res. 91: 46-53, 2002.
28. Zhu, W.Z., Wang, S.Q., Chakir, K., Kolbilka, B.K., Cheng, H., and Xiao,
R.P.: Linkage of 1-adrenergic stimulation to apoptotic heart cell death
through protein kinase A-independent activation of Ca2+/Calmodulin Kinase
II. J. Clin. Invest. 111:617-625, 2003.
29. Xiao, R.P., Zhang, S.J. Kuschel, M., Zhou, Y.Y., Bond, R.A., Balke, C.W.,
Lakatta, E.G., and Cheng, H.: Enhanced Gi signaling mediates the
diminution of -adrenergic contractile response in failing spontaneous
hypertensive rat heart. Circulation. 108:1633-1639, 2003.
30. Chakir, K., Xiang, Y., Zhang, S.J., Yang, D., Cheng, H., Kobilka, B.K., and
Xiao, R.P.: The third intracellular loop and the carboxyl terminus of
2-adrenergic receptor confer the receptor spontaneous activity. Mol.
Pharmacol. 64:1048-58, 2003.
31. Xiao, R.P., and Balke, C,W,: Na+/Ca2+ Exchange Linking 2-Adrenergic Gi
Signaling to Heart Failure: Associated Defect of Adrenergic Contractile
Support. J Mol. Cell. Cardiol. 36:7-11, 2004, (Editorial).
32. Ding, J.H., Xu, X., Yang, D., Chu, P.H., Dalton, N.D., Ye, Z., Yeakley, J.M.,
Cheng, H., Xiao, R.P., Ross, J., Chen, J., and Fu, X.D.: Dilated
cardiomyopathy caused by tissue-specific ablation of SC35 in the heart.
EMBO J. 23:885-96, 2004.
33. Patterson, A.J., Zhu, W., Chow, A., Kosek, J., Xiao, R.P., and Kobilka, B.K.:
Protecting the myocardium: A role for the 2-Adrenergic receptor in the
heart. Critical Care Medicine. 32:1041-8, 2004.
34. Xiao, R.P., Zhu, W., Zheng, M., Bond, R., Lakatta, E.G., and Cheng, H.:
Subtype-specific -adrenergic signaling pathways and their clinical
implications. Trends in Pharmacological Sciences (TiPS). 25: 358-365,
2004, (invited Review).
35. Pepe, S., van den Brink, O.W.V., Lakatta, E.G., and Xiao, R.P.:
-Adrenergic Receptor-Opioid Peptide Receptor Cross-talk: Cardiovascular
Regulation and Adaptation in Health and Disease. Cardiovascular Research.
15;63:414-22, 2004, (invited Review).
36. Chen, K.H., Guo, X.M., Ma, D.L., Guo, Y.H., Li, Q., Li, P., Qiu, X., Xiao,
R.P., & Tang, J.: Dysregulation of A Novel Hyperplasia Suppressor Gene
Triggers Vascular Proliferative Disorders. Nature Cell Biology, 6:872-83,
2004, (the corresponding author).
37. Leblais, V., Jo, S.H., Chakir, K., Maltsev, V., Zheng, M., Crow, M.T., Wang,
W., Lakatta, E.G., & Xiao, R.P. Phosphatidylinositol 3-Kinase Offsets
cAMP-Mediated Positive Inotropic Effect via Inhibiting Ca2+ Influx in
Cardiomyocytes. Circ. Res., 2004, 95:1183-90.
38. Zheng, M., Jo, S.H., Wersto, R., Han, Q., and Xiao, R.P.: Intracellular
Acidosis-Induced p38 MAPK Activation and Its Pathophysiological Relevance
in Cardiomyocyte Ischemia. FASEB J. 2005, 19:109-11.
二、Principal Investigator：程和平（He-ping Cheng）
Personal Synopsis
Heping (Peace) Cheng received degrees in applied mathematics and
mechanics, physiology, and biomedical engineering from Peking
University, China, where he served as a faculty member in the
Department of Electrical Engineering before earning his Ph.D.
degree in Physiology in 1995 from the University of Maryland at
Baltimore. He then joined the NIH Intramural Research Program as
a senior staff fellow in 1995 and was selected as a tenure-track
investigator in 1998. In November, 2004, he became a senior
investigator and the head of the Ca2+ Signaling Section in the
Laboratory of Cardiovascular Science, National Institute on Aging,
NIH. He is now a Senior Investigator and co-PI of the Calcium
Signaling Laboratory at IMM, PKU.
Research Interest
In my early years at Peking University, recognizing the power of
multidisciplinary integration, my mentors and I designed a unique
career path beginning with rigorous training in physiology,
mathematics, physics, and computer science. My dream was to pursue
fundamental biomedical questions by seamless integration of the
philosophy, theory, and craftsmanship of these different fields.
As a Ph.D. student at the University of Maryland at Baltimore,
I was fascinated with the economy and simplicity of Ca2+ in
biological systems. As a divalent cation, calcium undergoes
neither catabolism or anabolism, yet it plays pivotal roles in
nearly every aspect of biology. This paradox of simplicity and
complexity became even more profound as I realized that the list
for second messengers at work in any biological system is
extremely short–cAMP, IP3, ROS, for example. What mechanisms
bestow Ca2+, or any second messenger, with such amazing signaling
specificity and versatility?
In my first English publication, my co-workers and I reported the
discovery of "Ca2+ sparks" as the elementary events of
intracellular Ca2+ signaling. Ca2+ sparks are brief openings of
variable cohorts of from one to eight ryanodine receptor (RyR)
Ca2+ release channels in the endoplasmic or sarcoplasmic
reticulum (ER or SR). The summation of coordinated activation of
Ca2+ sparks in space and time gives rise to complex global Ca2+
signals.
Subsequent research in "sparkology" has unraveled exquisite
hierarchal architecture of Ca2+ signaling. On the basis of these
findings, we have proposed that Ca2+ signaling is, in essence,
a discrete, stochastic, and digital system, rather than a
continuous, deterministic, analog system, as previously thought.
This concept not only sheds new light on calcium’s complex
simplicity, but also allows for unprecedented precision in the
detection and definition of disease-related aberrant Ca2+
signaling.
In collaboration with M.T. Nelson, we uncovered a novel Ca2+
signaling pathway in which sparks relax vascular smooth muscles.
In this pathway, subsurface sparks activate large-conductance
Ca2+-sensitive K+ channels, which shut off L-type Ca2+ influx
through hyperpolarization of the membrane. This leads to
reduction of intracellular Ca2+ and muscle relaxation. This
finding vividly illustrates that a single simple messenger, Ca2+,
can serve different and even opposing roles in the same cell.
In heart muscle cells, Ca2+ entering through L-type Ca2+ channels
traverses a 12-nm junctional cleft to activate RyRs in the SR,
liberating stored Ca2+. This process is known as Ca2+-induced Ca2+
release (CICR). For years, many physiologists dreamed of "seeing"
nanoscale, intermolecular CICR. Our team has now painstakingly
accomplished the optical recording of single L-type channel Ca2+
currents or "Ca2+ sparklets." We went on to demonstrate that a
single sparklet can trigger a spark in an all-or-none fashion.
These steps made it possible to define the stoichiometry, kinetics,
and fidelity of intermolecular signaling in real time and in live
cells.
Most recently, we found that when a spark ignites, rapid and
substantial decreases in Ca2+, called "Ca2+ blinks," develop
within nanometer-sized stores–the junctional cisternae of the
SR. The complementary spark-blink signal pairs in heart may be
a prototype for similar reciprocal signals and suggest space-time
organization of signaling from Ca2+ stores, including capacitive
Ca2+ entry and ER/SR-dependent apoptotic signaling.
The aims of our current and future Ca2+ signaling research are
to discover new phenomena, functions, and mechanisms–leading to
new concepts and theories–as we develop novel methods, analytic
tools, special reagents, and instruments for Ca2+ studies. We hope
these "nuts and bolts" will broaden the frontier of technology
for the field.
We will continue to focus on Ca2+ signaling in subcellular
compartments and organelles (mitochondria, ER/SR, and nuclei) and
in vivo imaging of biosensors at single-cell and single-molecule
resolutions. But beyond this, we will consider the Ca2+ signalome
as a whole, including synthesizing information gleaned from
molecules, pathways, subcellular organelles, cells and organisms.
This integration enlists the powerful addition of bioinformatics
and system theory to our current research portfolio. In addition,
through collaboration, we also hope to translate our findings to
pertinent disease models, thereby advancing the understanding of
the etiology and enlightening the treatment of human diseases.
Selected Publuications
1. Cheng, H., Lederer, W.J., Cannell., M.B., 1993, Calcium sparks:
The elementary events underlying excitation-contraction coupling
in heart muscle. Science 262, 740-744
2. Cheng, H., Lederer, W.J., Cannell, M.B., 1995, Partial inhibition
of calcium current by D600 reveals spatial non-uniformities in
[Ca2+]i during excitation-contraction coupling in cardiac myocytes.
Circ. Res. 76, 236-241
3. Cheng, H., Fill, M., Valdivia, H.H., Lederer, W.J., 1995, Models
of calcium release channel adaptation, Science 267, 2009-2010
4. Cannell, M.B., Cheng, H., Lederer, W.J., 1995, The control of
calcium release in heart muscle. Science 268, 1045-1050
5. Nelson, M.T., Cheng, H., Rubart, M., Santana, L.F., Bonev, A., Knot,
H., Lederer, W.J., 1995, Relaxation of arterial smooth muscle by
calcium sparks. Science 270, 633-637
6. Klein, M.G., Cheng, H.*, Santana, L.F., Lederer, W.J., Schneider,
M.F., 1996, Discrete sarcomeric calcium release events activated
by dual mechanisms in skeletal muscle. Nature 379, 455-458 (* the
corresponding author)
7. Gomez, A.M., Valdivia, H.H., Cheng, H., Santana, L.F., Lederer,
W.J., 1997, Defective excitation-contraction coupling in
experimental cardiac hypertrophy and heart failure. Science 276,
800-806
8. Sham, J., Song, L.-S., Deng, L.H., Chen-Izu, Y., Lakatta, E.G.,
2+
Stern, M.D., Cheng, H., 1998, Termination of Ca release by local
inactivation of ryanodine receptors in cardiac myocytes. Proc. Natl.
Acad. Sci. USA 95, 15096-15101
9. Shirokova, N., Gonzalez, A., Kirsch, W.G., Rios, E., Pizarro, G.,
Stern, M.D., Cheng, H., 1999, Calcium sparks: release packets of
uncertain origin and fundamental role. J. Gen. Physiol. 113,
377-384 (Invited Review)
10. Wang, S.Q., Song, L.-S., Lakatta, E.G., Cheng, H., 2001, Ca2+
signalling between single L-type Ca2+ channels and ryanodine
receptors in heart cells. Nature 410, 592-596
11. Song, L.-S., Wang, S.Q., Xiao, R.-P., Spurgeon, H., Lakatta, E.G.,
Cheng, H., 2001, -adrenergic stimulation synchronizes
intracellular Ca2+ release during excitation-contraction coupling
in cardiac myocytes. Circ. Res. 88, 794-801
12. Song, L.-S., Guia, A., Muth, J., Rubio, M., Wang, S.Q, Xiao, R.-P.,
Josephson, I.R., Schwartz, A., Lakatta, E.G., Cheng, H., 2002, Ca2+
signaling in cardiac myocytes overexpressing the α1-subunit of
L-type Ca2+ channel. Circ. Res. 90, 174-181
13. Pan, Z., Yang, D., Nagaraj, R.Y., Nosek, T.A., Nishi, M. Takeshima,
H., Cheng, H., Ma, J., 2002, Dysfunction of store-operated Ca2+
channel in muscle cells lacking mg29 gene. Nature Cell Biol. 4,
379-383
14. Yang, D., Song, L.-S., Zhu, W.Z., Chakir, K., Wang, W., Wu, C.,
Wang, Y., Xiao, R.-P., Chen, S.R.W., Cheng, H., 2003, Calmodulin
regulation of excitation-contraction coupling in cardiac myocytes.
Circ. Res. 92, 659-667
15. Wang, S.Q., Stern, M.D., Ríos, E., Cheng, H., 2004,The quantal
nature of ca2+ sparks and in situ operation of the ryanodine receptor
array in cardiac cells. Proc. Natl. Acad. Sci. USA 101, 3979-3984
16. Wang, S.Q., Wei, C.L., Gao, G. L., Brochet, D., Shen, J.X., Song,
L.S., Wang, W., Yang, D.M., Cheng, H., 2004, Imaging microdomain
Ca2+ in muscle cells. Circ. Res. 94, 1011-1022 (invited review)
17. Wang, W., Zhu, W., Wang, S. Q., Yang, D. M., Crow, M. T., Xiao,
R. P., Cheng, H., 2004, Sustained 1-adrenergic stimulation
modulates cardiac contractility by Ca2+/calmodulin kinase signaling
pathway. Circ. Res. 95,798-806.
18. Brochet, D. X. P., Yang, D., Di Maio, A., Lederer, W. J.,
Franzini-Armstrong, C., Cheng, H., 2005, Calcium blinks: Rapid
nanoscopic store calcium signaling. Proc. Natl. Acad. Sci. USA, 102,
3099-3104
19. Ouyan, K., Wu, C. H., Cheng, H. (2005) Ca2+-induced Ca2+ release in
sensory neurons: Low-gain amplification confers intrinsic
stability. J. Biol. Chem. 280, 15898-15902
20. Wang, X., Collet, C., Weisleder, N., Zhou, J.S., Chu, Y., Brotto, M.,
Hirata, Y., Pan, Z., Cheng, H., Ma, J. (2005) Uncontrolled Ca2+
sparks as dystrophic signal for mammalian skeletal muscle.
Nature Cell Biol. 7, 525-530
三、Principal Investigator：周专（ Zhuan
Personal Synopsis
Zhou）
Zhuan Zhou, 1984, B.S. Electronic instrumentation, Tongji
University, Shanghai. 1990, Ph.D. (Prof. Huaguang Kang's lab)
Biomedical Engineering, Huazhong University of Science and
Technology (HUST), Wuhan. Nov. 1990-Feb. 1993, postdoctoral
fellow (Dr. Erwin Neher's lab), Max-Planck-Institute for
Biophysical Chemistry, Goettingen, Germany. Feb. 1993 - Oct.
1995, Research Instructor (Dr. Stanley Misler's lab), Departments
of Physiology, Washington University. St. Louis, USA. Nov.
1995-97, Researcher Assistant Professor, Department of
Physiology, Loyola University, Chicago, USA. Sep. 1997-99,
professor and head, Department of Neuroscience and Biophysics,
University of Science and Technology of China, Hefei. Apr.
1993-2000, professor and director, Nov. 1999-2004, Principle
Investigator, Institute of Neuroscience, Chinese Academy of
Sciences. Consul of Biophysical Society of China, Chair of
Neurobiophysics Committee (2002-2006). Consul of Chinese
Association of Physiological Society (2002-2006). He is now a
Senior Investigator and PI of the Nerve-Circulation-interaction
Laboratory at IMM, PKU.
Research Interests
Secretion is a principle function of a cell. Neurotransmitter
and hormone secretion is triggered by increase in intracellular
Ca concentration. We are interested in mechanisms of how
intracellular Ca is regulated in single cell level by advanced
methods including electrophysiological and optical fluorescence
measurements. We investigate mechanisms of neurotransmitter, in
particular catecholamines, release from soma (or synapse) of a
cell by patch-clamp, membrane capacitance and carbon fiber
electrodes (CFEs) and fluorescent optic measurements. We are
interested in creating/modifying biophysical technologies for
advanced experiments including Ca homeostasis, patch-clamp and
stimulus-secretion-coupling. Our goal is to best understand how
secretion is regulated in a living cell, and how catecholamine
release (from adrenal chromaffin cells as well as
catechonminergic CNS neurons, affect cardiac/vesicular function.
Ionic channels, action potentials and quantal secretion in single
cells
Neurotransmitter release is primary triggered by Ca influx during
action potentials in neuronal cells. Action potentials are
generated and regulated by variety of ion channels on the cell
membrane. We are interested in how action potential patterns are
regulated by the ion channels, and how secretion is regulated by
different encodes of the action potentials. We created a technique
for membrane capacitance measurements using reconstituted codes
of action potentials as stimulation protocol and we are studying
the relation between action potential pattern and cell secretion
in chromaffin cells.
We are interested in the kinetics of fusion pore, which
release/uptake vesicle contents during an exocytotic/endocytotic
event. In adrenal chromaffin cells, we discovered that the
endogenous transmitter ATP can inhibits secretion via two
pathways: Ca channel (50% of total inhibition) and fusion pore
(the other 50% of total inhibition). ATP reduces the fusion pore
open time or shift the mode of exocytosis to “kiss-and-run”.
In astrocyte, a hippocampal glia, we study Ca dependent quantal
secretion as well. In particular, the fusion pore kinetics in
astrocytes is distinct in response to different stimulations.
Ion channels are molecular basis for action potentials. Ion
channels studies in our lab including Na channel (inactivation),
voltage and Ca dependent K channels (specific toxins against BK
and SK channels) and HCN pacemaker channels. The role of HCN (or
If, Ih) channels is to generate rhythmic action potentials in the
host cells. In opposite to other voltage gated channels, these
channels activate at negative potentials and thus depolarize the
cell to fire next Na dependent action potential. This
non-selective cation channel has a reversal potential at —30-40
+
+
mV and permeates Na and K . Recently, we discovered that in
2+
addition to mono cation, HCN can permeate Ca as well: 05% of total
2+
current is contributed by Ca . The Ca influx through Ih channels
can modulate neuronal secretion in DRG neurons and action
potential duration in cardiac cells.
Exocytosis and endocytosis in somata in DRG neurons
In sensory dorsal root ganglion (DRG) neurons, we have discovered
a novel type of action potential triggered secretion in the soma,
Ca independence but voltage dependent secretion (CIVDS). This
means, depolarization can directly trigger exocytosis in the
2+
absence of both internal and external Ca . This finding was very
surprising in the areas of stimulus-secretion coupling and
synaptic transmission, because the dominant “Ca hypothesis”
2+
puts Ca as the only trigger for exocytosis, the role of voltage
depolarization is only to allow Ca influx through voltage gated
Ca channels. CIVDS can be detected by membrane capacitance,
electrochemical amperometry, and confocal single vesicle imaging
assays. In DRG soma, membrane depolarization/action potential
trigger both Ca dependent secretion (CDS) and CIVDS. Vesicle
pool size of CIVDS is 20 % of that of CDS. After depletion of the,
the recovery rate of the vesicle pool of CIVDS is fast (10 s).
Compared with CDS, the onset rate of CIVDS is very fast. The
voltage dependence of CIVDS is similar as a voltage-sensitive ion
channel. These properties make CIVDS to be the major source of
secretion in response to in low (< 5 Hz) frequency action
potentials.
Under physiological conditions, the low frequency of action
potential may trigger
Following CIVDS, there is a rapid endocytosis termed
CIVDS-RE. Compared to other endocytosis in neurons, CIVDS-RE has
several distinct properties: (1) like CIVDS, RE is Ca independent;
(2) RE is dynamin independent; (3) RE depends on frequency of
action potentials; (4) RE is dependent of PKA, which is activated
by high (not low) frequency of action potentials.
In addition to voltage-triggered exocytosis and endocytosis,
we are interested in ligand-triggered exocytosis and endocytosis.
2+
Compared to Ca influx through Ca channels, the caffeine
sensitive Ca stores (or Ca sparks) alone have a lower efficiency
to trigger secretion. However, Ca stores provide an important
synergistic role to enhance depolarization induced secretion.
Finally, we are studying ligand-induced endocytosis and their
signal tranduction with high spatial and temporal resolution by
using capacitance and single vesicle imaging. These studies may
have potential applications in GPCR-mediated signaling in neurons
and cardiac cells.
Stimulus-secretion-coupling between neurons in the brain slice and in
living brain
Currently, majority studies on stimulus-secretion-coupling are
performed in culture cells. This is because the culture cells
offer relative simple techniques to record secretion in single
cells. However, interaction between neurons and other cell
environment maintain better in brain slice or in vivo. To
understand how synaptic transmission and cell secretion occur in
brain slice and/or in vivo, we are developing new carbon fiber
electrodes (CFEs) and studying neurotransmitter release in slice
and in living animals. We determine the common and different
features of stimulus-secretion coupling between neurons in
culture, in slice and in vivo. These studies may lead new insights
into exocytosis/endocytosis in response to stimuli under more
physiological conditions.
Development of novel microprobes to detect neuropeptides secretion
from single cells with high spatial-temporal sensitivity
Neuropeptides are important modulators for fundamental
brain functions. Unlike other ligands such as ACh, glutamate
etc, there are few neuropeptide-gated ion channels, which can
be recorded by patch-clamp. Thus, to detect neuropeptide
new probes are needed. Since several years we are working
on new types of electrodes, which may sense release of
neuropeptides. Our goal is to use the new
peptide-electrodes to study how, when and where
neuropeptides are released from culture single cells, brain
slices and living brains.
.
Selected Publuications
1. Chen
Zhang, Wei Xiong, Hui Zheng, Liecheng Wang, Bai Lu and Zhuan Zhou
(2004) Calcium- and dynamin-independent endocytosis in dorsal root
ganglion neurons. Neuron, 42: 225—236
2. Yu
X, Duan KL, Shang CF, Yu HG and Zhou Z (2004) Calcium influx through
hyperpolarization-activated cation channels ( Ih channels) contributes
to activity-evoked neuronal secretion. Proc Natl Acad Sci U S A.,
101:1051-1056.
3. Duan
KL, Yu X, Zhang C, and Zhou Z (2003) Control of Secretion by Temporal
Patterns of Action Potentials in Adrenal Chromaffin Cells. J. Neurosci.,
23(35):11235-43
4. Xuelin
Lou, Xiao Yu, Xiao-Ke Chen, Liming He, Kai-Lai Duan, Anlian Qu,
Tao Xu and Zhuan Zhou. (2003) Na channel inactivation: a comparison study
between pancreatic islet ？-cells and adrenal chromaffin cells in rat.
J. Physiol (Lond) 548: 191-202.
5. Chong-Xu
Fan, Xiao-Ke Chen, Chen Zhang, Li-Xiu Wang, Kai-Lai Duan,
Lin-Lin He, Ying Cao1,
Shang-Yi Liu, Ming-Nai Zhong, Chris Ulens, Jan
Tytgat, Ji-Sheng Chen, Cheng-Wu Chi and Zhuan Zhou. (2003) A Novel
Conotoxin from Conus betulinus, -BtX, unique in Cysteine Pattern and
in Function as a specific BK Channel Modulator. J. Biol. Chem.
278:12624-33
6. Lan
Bao, Shan-Xue Jin, Chen Zhang, Li-Hua Wang, Zhen-Zhong Xu,Fang-Xiong
Zhang, Lie-Chen Wang, Feng-Shou Ning, Hai-Jiang Cai, Ji-Song Guan,
Hua-Sheng Xiao, Zhi-Qing D. Xu, Cheng He, Tomas Hokfelt, Zhuan Zhou# and
Xu Zhang# (2003) Activation of delta-Opioid Receptors on Dorsal Root
Ganglion Neurons Induces Receptor Insertion and Neuropeptide Secretion.
Neuron, 37:121-133. (# co-corresponding Authors)
7. Yong-Hua
Ji, Jian-Guo Ye, Wei-Xi Wang, Lin-Lin He, Ya-Jun Li, Yan-Ping
Yan, Chen Li, Zhi-Yong Tan, Zhuan Zhou. (2003) BmTX3, a Novel Specific
Blocker of Ca2+-Activated K+ Channel from Asian Scorpion Venom:
Purification, Genomic Organization and Function Assessment. J.
Neurochem. 84(2):325-35.
8.
Zhou.Z & Bers.DM (2002) Time Course of Mitochondrial Antagonists Blockade
in Intact Cells. European Journal of Physiology, 445:132-138
9. Zhang
C & Zhou Z (2002) Ca2+-independent but voltage-dependent secretion
in mammalian dorsal root ganglion neurons. Nature Neuroscience,
5(5):425-30
10.Zhou.Z
& Bers.DM (2000) Ca influx via L-type Ca channel at voltages
positive to the reversal potential in ventricular myocytes. Journal of
Physiology (London) 523: 57-66
11.Zhou.Z
, Matlib.MA & Bers.DM (1998) Cytosolic and mitochondrial Ca2+
signals in patch clamped mammalian ventricular myocytes. Journal of
Physiology (London), 507：379-403
12.Matlib,
Z. Zhou, S. Knight, S. Ahmed, K. Choi, J. Krause-Bauer, R.
Phillips, R.Altschuld, Y. Katsube, N. Sperelakis, D. Bers (1998)
Oxo-Bridged Dinuclear ruthenium Ammine Complex Specifically inhibits
Ca2+ Uptake into mitochendria in vitro and in situ in single cardinac
myocytes. J. Biol. Chem.273(17):10223-31,
13.A.Elhamdani
,Z.Zhou & CR.Arttalejo (1998) Timing of dense-core vesicle
exocytosis depends on the facilitation L-type Ca channel in adrenal
chromaffin cells. J. Neurosci. 18(16):6230-40
14.Zhou.Z,
Misler.S & Chow .RH (1996) Rapid fluctuations in transmitter
release from single vesicles in bovine adrenal chromaffin cells.
Biophysical Journal, 70:1543-52
15.Zhou.Z,
Misler.S (1996) Amperometric detection of quantal secretion
from patch-clamped rat pancreatic beta-cells. J Biol Chem 271(1):270-7
16.Zhou.Z,
Misler.S (1995) Amperometric detection of stimulus-induced
quantal release of catecholamines from cultured superior cervical
ganglion neurons. Proc Natl Acad Sci USA 92(15):6938-42
17.Burnashev,
N., Zhou, Z., Neher, E. & Sakmann, B. (1995) Calcium flux
and fractional calcium currents through recombinant GluR channels of
NMDA-R, AMPA-R and KA-R Subtypes. J. Physiol. (London), 485:403-418
18.Zhuan
Zhou & Stanley Misler (1995) Action potential induced
catecholamine secretion in rat chromaffin cells. Journal of Biological
Chemistry, 270: 3498-3505.
19.Zhuan
Zhou & Erwin Neher (1993). Mobile and immobile Ca buffers in bovine
adrenal chromaffin cells. J. Physiol. (London). 469: 245-273
20.Schneggenburger,R.,
Zhou,Z., Konnerth,A. & Neher,E. (1993). Fractional
contribution of calcium to the cation current through glutamate
receptors. Neuron, 11: 133-143
四、Principal
Investigator：梁子才（Zi-cai
Liang）
Personal Synopsis
Zicai Liang was trained as a biologist at Nankai University where
he received his B.Sc. and M.Sc. degrees and then as a molecular
Biologist at Uppsala University where he obtained his Ph.D. degree
in 1995. He then spent 3 years in Yale University as a postdoc
working on Drosophila molecular genetics. In end of 1998 he moved
to Karolinska Institute, Sweden to start his own group working
on Genomics technologies as an Assistant Professor. He has also
served as director of the Karolinska Institute DNA chip core
facility (KICHIP). He also served as founder and director of
several biotech companies in Sweden. In 2004, he was awarded the
title of associate professor (docent) at Karolinska Institute.
He has also been a visiting Professor at Chinese Human Genome
Center North since 2003. He is now an Investigator and PI of the
Laboratory of Nucleic Acid Technologies at IMM, PKU.
Research Interest
The scope of my research work and interests cover several aspects
of the modern biotechnologies: (I) RNA interference, including
siRNA methodology development, high throughput screening, in vivo
delivery, and siRNA drug development; (II) high throughput
library methodologies with emphasis on siRNA, and peptide level;
(III) functional assessment of non-coding RNA, including microRNA,
natural antisense RNA, riboswitches, and artificial aptamers; (IV)
GPCR ligand screening using nucleic acid tools.
Over the last 6 years, we have created several leading technology
platforms in the research area of DNA chips, antisense technology
and recently siRNA technology. The research work has led to many
patent applications that end up with the founding of three biotech
companies.
Selected Publications
1. S. Katayama, Y. Tomaru, T. Kasukawa, K. Waki, M. Nakanishi, M. Nakamura,
H. Nishida, C. C. Yap, M. Suzuki, J. Kawai, H. Suzuki, P. Carninci, Y.
Hayashizaki, C. Wells, M. Frith, T. Ravasi, K. C. Pang, J. Hallinan, J. Mattick,
D. A. Hume, L. Lipovich, S. Batalov, P. G. Engstrom, Y. Mizuno, M. A. Faghihi,
A. Sandelin, A. M. Chalk, S. Mottagui-Tabar, Z. Liang, B. Lenhard, C.
Wahlestedt (2005) Antisense transcription in the mammalian transcriptome.
Science 309, 1564-1566
2. Meihong Chen, Quan Du, Hong-Yan Zhang, Claes Wahlestedt and Zicai
Liang* (2005) Vector-based siRNA delivery strategies for high-throughput
screening of novel target genes. Journal of RNAi and Gene Silencing 1, 5-11
(invited review)
3. Quan Du, Ola Larsson and Harold Swerdlow, Zicai Liang* (2005) DNA
immobilization: silanized nucleic acids and nanoprinting. (Book chapter in
volume "Immobilisation of DNA on Chips" within the Series "Topics in
Current Chemistry" ed. By Christine Wittmann)
4. Quan Du*, Claes Wahlestedt and Zicai Liang* (2005) Dissection of
specificity of a siRNA towards all target sites with one nucleotide mismatches
Nucleic Acids Res. 33,1671-1677.
5. Joacim Elmen, Hakan Thonberg, Karl Ljungberg, Miriam Frieden, Yunhe Xu,
Britta Wahren, Zicai Liang, Henrik Orum, Troels Koch and Claes Wahlestedt
(2005) Locked Nucleic Acid (LNA) mediated improvements in siRNA
functionality. Nucleic acids Res. 33, 439-447
6. Meihong Chen, Lishu Zhang, Hong-Yan Zhang, Xiahui Xiong, Bo Wang, Quan
Du, Bing Lu, Claes Wahlestedt, and Zicai Liang* (2005) A Universal Plasmid
Library Encoding All Permutations of siRNA. Proc. Natl. Acad. Sci. USA 120,
2356-2361.
7. Joacim Elmen, Hong-Yan Zhang, Bartek Zuber, Britta Wahren, Claes
Wahlestedt and Zicai Liang (2004) Locked nucleic Acids (LNA) inhibit HIV
replication by blocking viral genome dimerization. FEBS Letter, 578,
285-290
8. Quan Du, Hakan Thonberg, Hong-Yan Zhang, Claes Wahlestedt, and Zicai
Liang* (2004) Validating siRNA using a reporter made from synthetic DNA
oligonucleotides. Biochem Biophys Res Commun. 325, 243-249
9. Jianping Mao, Zicai Liang and Binzhi Mao (2004) For mRNA accessible sites
screening: a comparative study by using MAST and computational prediction.
Chinese J. Biochem. Mol. Biol. 20, 399-407
10. Yunhe Xu, Annika Linde, Ola Larsson, Dorit Thormeyer, Joacim Elmén, Claes
Wahlestedt and Zicai Liang* (2004) Functional comparison of single- and
double-stranded siRNAs in mammalian cells. Biochem. Biophys. Res.
Commun. 316, 680-687
11. Ola Larsson*, Camilla.Scheele, Zicai Liang*, Christina Karlsson, Jurgen
Moll and Claes Wahlestedt (2004) Transcriptional analysis of scenescence
process using a mouse temperature sensitive SV40 T-antigen senescence
model. Cancer Research 64, 482-489 (* co-corresponding authors)
12. Xu Y, Zhang HY, Thormeyer D, Larsson O, Du Q, Elmen J, Wahlestedt C,
Liang Z.* (2003) Effective small interfering RNAs and phosphorothioate
antisense DNAs have different preferences for target sites in the luciferase
mRNAs. Biochem Biophys Res Commun. 306, 712-717
13. Zhang H., Mao J., Zhou D., Xu Y., Thorberg H., Liang Z.,* and Claes
Wahlestedt* (2003) mRNA accessible site Tagging(MAST): a novel method
of selecting effective antisense oligonucleotides. Nucleic Acids Research 31,
e72-e72 (* co-corresponding authors)
14. Thormeyer D., Ammerpohl O., Larsson, O., Xu Y., AsingerA., and Liang Z*.
(2003) Characterization of a novel pair of lacZ complementation deletions
using membrane receptor dimerization as a model. BioTechniques 34,
346-355
15. Larsson O., Thormeyer, D., Asinger A., Wihlen B., Wahlestedt C. and Liang
Z*. (2002) Quantitative codon optimisation of DNA libraries encoding
sub-random peptides: design and characterisation of a novel library
encoding trans-membrane domain peptides. Nucleic Acids Research 30,
e133-e133.
16. Kumar A., and Liang Z.* (2001) Chemical nanoprinting: a novel method for
fabricating DNA microchips. Nucleic Acids Res. 29, e2-e2
17. Wang R, Liang Z, Hall M, Soderhall K. (2001) A transglutaminase involved in
the coagulation system of the freshwater crayfish, Pacifastacus leniusculus.
Tissue localisation and cDNA cloning. Fish Shellfish Immunol. 11, 623-37.
18. Kumar A., Larsson O., Parodi D., and Liang Z.* (2000) Silanized nucleic
acids: a general platform for DNA immobilization. Nucleic Acids Res. 28,
e71-e71
19. Liang Z. and Biggin M.D. (1998) Homeodomain protein Eve binds and
regulates a wide range of genes during embryogenesis in Drosophila.
Development 125, 4471-4482
20. Liang Z., Hall M., Sottrup-Jensen L. Aspan A. and Soderhall K. (1997)
Pacifastin, a novel 155 kDa heterodimeric proteinase inhibitor with a unique
three-domain transferrin chain. Proc. Natl. Acad. Sci. 94, 6682-6687
五、Principal
Investigator：李建（Jian
Li）
Jian Li obtained her M.D. in
Beijing University of Chinese Medicine in 1983. Following
clinical resident training in Beijing, she pursued a graduate
study in cell and molecular biology and received her Ph.D. degree
at the Upstate Medical Center, State University of New York in
1992. She jointed in the Cardiovascular Research Laboratory in
Harvard School of Public Health as a post-doctoral fellow, then,
became an Instructor of Medicine in the Angiogenesis Research
Center, Beth Israel Deaconess Medical Center, Harvard Medical
School in 1996. She was promoted to Assistant Professor of
Medicine in Harvard Medical School as an independent principal
investigator in 2002. She is now a Professor, Senior
Investigator and head of the Angiogenesis Research Center at IMM,
PKU.
Research History:
Dr. Li has been engaged in both clinical and basic research in
cardiovascular disease since receiving her medical clinical and
biomedical research trainings. Her Ph.D. thesis in Dr. Larry
Lemanski's laboratory examined morphology and function of
cytoskeletal proteins in cardiomyopathic hearts with a particular
emphasis on function of intermediate filaments. In her
post-doctoral training in the laboratory of Dr. Eager Haber in
the Cardiovascular Research Center, she focused on analyses of
vascular endothelial growth factor (VEGF) expression, a potent
and specific mitogen for vascular endothelial cells and promoter
neovascularization in animal model of arteriosclerosis in vivo
and endothelial, smooth muscle cells in vitro. The results of
these studies were published both Journal of Biological Chemistry
and Journal of Clinical Investigations as the one of the early
publications of growth factors in angiogenesis study. In the
Angiogenesis Research Center directed by Dr. Michael Simons in
BIDMC, Harvard Medical School, Dr, Li's research consistently
concentrated on determining the effect of heparin-binding growth
factors, VEGF, FGF and peptide, PR39 in angiogenesis with
transgenic mice and myocardial ischemia model. She has published
several first author manuscripts in leading journals including
American Journal of Physiology, Journal of Clinical
Investigations, Circulation Research and Nature Medicine and
co-authored more publications in this field.
Research Interests:
Gene regulation and gene therapy of angiogenesis in myocardial
ischemia
Angiogenesis is a complex process involving endothelial cell
proliferation and migration, and the formation of new blood
vessels from the preexisting vascular bed. Angiogenesis is of
paramount importance in the maintenance of vascular integrity,
both in the repair of damaged tissue and in the formation of
collateral vessels in response to tissue ischemia. Thus,
angiogenesis has been proven as a beneficial process in ischemic
coronary disease. While proximal occlusion of an epicardial
coronary artery leads to ischemia of the distant coronary bed and
subendocardial myocardium, epicardial collaterals frequently
develop around the site of occlusion nonischemic area. Therefore,
stimuli other than hypoxia, such as shear stress and ongoing
inflammation, can also be involved in collateral development. In
contrast to that observed in large collaterals, increased
capillary density is seen more frequently in areas of actual
ischemia, which may be attributed to the hypoxia-mediated
increase in endothelial mitogens and their receptors.
Considering cancer cell development is dependent on angiogenesis,
the both up- and down-regulation of angiogenic genes are important.
Therefore, in future plan, we will set up the angiogenesis
research in two directions: 1) Angiogenesis in myocardial
ischemia; 2) Anti-angiogenesis in control of cancer cell
development.
Specifically, the research focus on:
A. To understand the cross-talk between cardiac myocytes and
endothelial cells, focusing on myocytes-dependent gene
regulation in endothelial cells in response to hypoxia and
ischemia. The project will include the investigation
hypoxia-induced molecules from cardiac myocytes targeting to
endothelial cells to induce the regulation of gene and proteins
correlated to signaling tranduction pathway and chemotaxis in
terms of angiogenesis.
B. Hypoxia-induced transcriptional factors in regulation
angiogenic genes in ischemic cardiovascular disorder. We
investigate the role of Related Transcription Enhance Factor-1
(RTEF-1) in regulation angiogenic genes such as VEGF, FGF-2 and
the receptors in hypoxic endothelial cells.
C. The feasibility of delivering Endothelial Progenitor Cells
(EPCs) into myocardial ischemic heart to a decrease in infarct
size and improvement in ventricular function. The research is
focused on Stromal Cell-Derived Factor-1α (SDF-1α), a strong
EPC chemoattractant, homes EPCs to promote their differentiation
along the endothelial lineage. The approaches are involved in this
project are that transplantation of EPCs after myocardial
infarction in mice to determine that EPCs could traffic through
the coronary system into injured myocardium and incorporate into
angiogenic vessel.
D. The cellular mechanisms of nature medicine in vasodilatation,
angiogenesis and myocardial ischemia. In collaboration with a
Harvard chemistry laboratory, we work on the effect of compounds
extracted for nature medicine (Chinese Herbs) in cardiovascular
disorders. Specifically, we will utilize several methods,
including a microarray-based genomics approach and
high-throughput screening approach, to determine the range of
vasodilatation and angiogenesis in endothelial cells. By using
our established endothelial hypoxia and myocardial ischemia model,
we anticipate to discovery new therapeutic way in cardiovascular
disease.
Selective Publications:
1.
Li J, Robertson RD and Lemanski LF. (1990) Abnormalities in myofibril
organization and cell shape in developing cardiomyopathic hamster
heart cell in culture. Anna. New York Acad. Sci. 588: 412-416.
2.
Li J and Lemanski LF. (1990) Immunofluorescent studies for -actinin
on cultured cardiomyopathic hamster heart cell. Anat. Rec. 228:
46-52.
3.
Wang HZ, Li J, Lemanski LF and Veenstra RD. (1992) Gating of mammalian
cardiac gap junction channels by transjunctional voltage. J.
Biophysics.63: 139-151.
4.
Li J, Robertson RD and Lemanski LF. (1994) Morphometric analysis of
cultured normal and cardiomyopathic hamster heart cells after
immunofluorescent staining for tubulin and -actinin. Acta
histochemica. 96: 857-859.
5.
Li J, Perrella M, Tsai JC, Hsieh CM, Yoshizumi M, Patterson C, Endege
WO, Zhou F, Lee ME and Haber E. (1995) Induction of vascular endothelial
growth factor gene expression by interleukin-1 in rat aortic smooth
muscle cells. J. Bio. Chem. 270:308-312
6.
Yoshizumi M, Hsieh CM, Tsai JC, Li J, Perrella M, Patterson C, Endege
WO, Lee ME and Haber E. (1995) Disappearance of cyclin A correlates
with Permanent Withdrawal of cardiomyocytes from the cell cycle in
human and rat hearts. J. Clin. Invest. 95: 2275-2280.
7.
Li J, Brown LF, Hibberd MG, Grossman JD, Morgan JP and Simons M. (1996)
VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model
of angiogenesis. Am. J. Physiol. 270:H1803-H1811
8.
Harada K, Friedman M, Lopez JJ, Wang SY, Li J, Prasad PV, Pearlman
JD, Edelman ER, Sellke FW and Simons M. (1996) Vascular Endothelial
Growth Factor Administration in chronic myocardial ischemia. Am. J.
Physiol. 270:H1791-H1802.
9.
Sellke FW, Wang SY, Stamler A, Lopez JJ, Li J. Li JY and Simons M.
(1996) Enhanced microvascular relaxations to VEGF and bFGF in
chronically-ischemic porcine myocardium. Am. J. Physiol.
271:H713-720.
10. Li J, Hampton TG, Morgan JP and Simons M. (1997) Stretch-induced VEGF
expression in rat heart. J. Clin. Invest. 100 (1): 18-24.
11. Li J, Brown LF, Laham RL, Volk R and Simons M. (1997)
Macrophage-dependent regulation of syndecan gene expression. Circ.
Res. 81 (5): 785-796
12. Metais C, Li JY, Li J, Simons M and Sellke FW. (1998) Effects of
coronary artery disease on expression and microvascular response to
VEGF. Am. J. Physiol. 275:H1411-H1418.
13. Tofukuji M, Metais C, Li J, Frankline A, Simons M and Sellke FW. (1998)
Myocardial VEGF expression after cardiopulmonary bypass and
cardioplegia. Circulation: II-242-II-248.
14. Tofukuji M, Metais C, Li JY, Hariawala MD, Frankline A, Vassileva C,
Li J, Simons M and Sellke FW. (1998) Effects of ischemic
preconditioning on myocardial perfusion, function and microvascular
regulation. Circulation. 98: II-197-II-205.
15. Metais C, Li J, Li JY, Simons M and Sellke FW. (1999).
Serotonin-induced coronary contraction increase after blood
cardioplegia-reperfusion. Circulation: 100 [suppl II] II-328-II-334.
16. Volk R, Schwartz J J, Li J, Rosenberg RD and Simons M. (1999) The Role
of Syndecan Cytoplasmic Domain in bFGF-Dependent Signal Transduction.
J. Biol. Chem. 274: 24417-24424
17. Li J, Post M, Volk R, Gao Y, Li M, Metais C, Sato K, Tsai J, Aird W,
Rosenberg RD and Simons M. (2000) PR-39, a peptide regulator of
angiogenesis. Nature Medicine. Jan. 2000, 49-55.
18. GaoY, Lecker S, Post M, Hietaranta A, Li J, Volk R, Li M, Sato K, Saluja
A, Steer M, Goldberg A and Simons M. (2000) Inhibition of
Ub-proteasome-mediated I？B？？ degradation by a naturally occurring
antibacterial peptide: novel mode of regulation of NF？B-dependent
gene expression. J Clin Invest 2000; 106:439-48
19. Hampton TG, Amende I, Fong J, Laubach V, Li J, Metais C, and Simons
M (2000) Basic FGF reduces stunning via a NOS2-dependent pathway in
coronary-perfused mouse hearts. Am. J. Physiol
279: H260-H268.
20. Metais C, Bianchi C., Li J, Li JY, Simons M and Sellke FW. (2001)
Serotonin-induced human coronary microvascular contraction during
acute myocardial ischemia is blocked by COX-2 inhibition. Basic Res
Cardiol. 96(1): 59-67.
21. Xu X, Li J, Li JY, Laham R, Simons M and Sellke FW (2001) Expression
of VEGF and its receptors in increased but microvascular relaxation
is impaired in patients after acute myocardial ischemia. J Thorac
Cardiovasc Surg. 2001 Apr; 121(4): 735-42.
22. Li J, Parovian C, Hampton TG, Li JY, Metais C, Tkachenko E, Sellke
FW, Simons M (2002) Effect of vascular relaxation by cell surface
heparan sulfate and increase of nitric oxide release in response to
FGF2 in ？MHC-syndecan4 over-expression mice. Microvascular Res. Jul;
64(1): 38-46.
23. Li J, Shworak NW, and Simons M. (2002) Increased responsiveness of
hypoxic endothelial cells to FGF2 is mediated by HIF-1？-dependent
regulation of enzymes involved in synthesis of heparan sulfate FGF2
binding sites. J. Cell Science. 115: 1951-1959.
24. Huang X, Li J, Foster D, Lemanski S, Zhang C and Lemanski L. (2002)
Protein kinase C mediated desmin phosphorylation is related to
myofibril disarray in cardiomyopathic hamster heart. Exp Biol Med
(Maywood). 227(11): 1039-46.
25. Laham RJ, Li J, Tofukuji M, Post M, Simons M and Sellke FW (2003)
Spatial Heterogeneity in VEGF-induced Vasodilation: VEGF Dilates
Microvessels but Not Epicardial and Systemic Arteries and Veins Ann
Vasc Surg 17(3): 245-52.
26. Ruel M, Wu GF, Khan TA, Voisine P, Bianchi C, Li J, Li J, Laham RJ,
Sellke FW. (2003) Inhibition of the cardiac angiogenic response to
surgical FGF-2 therapy in a Swine endothelial dysfunction model.
Circulation. 2003 Sep 9, 108 Suppl 1:II335-40
27. Wu GF, Mannam A, Kirbis S, Wu J, Laham RJ, Sellke FW and Li J (2003)
Hypoxia Induces Myocyte-dependent COX-2 Gene Regulation in Human
Vascular Endothelial Cells. Am. J. Physiol 285: H2420-H2429
28. Finsen AV, Woldbaek PR, Li J , Wu J, Lyberg T, Tonnessen T, and
Christensen J. (2004) Increased Syndecan Expression Following
Myocardial Infarction Indicates a Role in Cardiac Remodeling.
Physiol. Genomics 16: 302-308.
29. Wu, JP, Parungo C, Wu GF, Kang PM, Laham RJ, Sellke FW, Simons M and
Li J. (2004) PR39 Inhibits Apoptosis in Hypoxic Endothelial Cells-Role
of Inhibitor Apoptosis Protein-2. Circulation 109(13):1660-7
30. Shie JL, Wu GF, Wu JP, Liu FF, Laham RJ, Oettgen P and Li J. (2004)
RTEF-1, a Novel Transcriptional Stimulator of VEGF in Hypoxic
Endothelial Cells. J. Bio. Chem. In Press.
六、Principal
Investigator：沈幼棠（You-tang
Shen）
Prof. You-tang Shen is a world leader on non-human primate
research in cardiovascular medicine. In 1970’s while working
in a hospital in Shanghai, he taught himself cardiovascular
medicine, and invented a number of methods and instruments for
the diagnosis of cardiovascular diseases. Between 1985 and 1994,
he has been in Department of Medicine, Harvard University, where
he played an essential role in the establishment of a superb
research program on animal models (including non-human primate)
of cardiovascular diseases. In the next 10 years (1994-2004), he
led the Primate Research team at Merck Research Laboratories. He
is currently a Senior Investigator at Institute of Molecular
Medicine, Peking University, and Professor and Director at
Physiology Section, Cardiovascular Research Institute,
University of Medicine and Dentistry of New Jersey. His direct
contributions to cardiovascular research are reflected by over
100 scientific publications and numerous patents. His current
research and educational interests include training a talented
Chinese team of primate research, using primate models to study
mechanisms of cardiovascular dysfunction and remodeling,
cardiovascular aging, cardiac apoptosis and regeneration, and the
evaluation of drug, gene and cell therapies of cardiovascular
diseases.