Summer Project 1: Metabolism in the right ventricle in pulmonary hypertension:
The function of the right ventricle (RV) is a major determinant of prognosis in patients with
pulmonary arterial hypertension (PAH) and congenital heart disease. RV hypertrophy (RVH)
occurs in RV pressure overload and, while initially compensatory, often leads to RV failure (RVF).
There is an emerging recognition that not all forms of RVH are identical. Some patients develop
concentric RVH and retain RV function and good functional capacity (which we term adaptive
RVH); others (despite identical pressure overload) develop maladaptive RVH, marked by RV
dilatation, fibrosis and RVF. There are several differences between adaptive and maladaptive
RVH including greater ischemia and adrenergic remodeling in maladaptive RVH. However, this
proposal focuses on a consistent and plastic abnormality that accompanies RVH and which
adversely affects RV function-namely inhibition of pyruvate dehydrogenase (the mitochondrial
enzyme which regulates glucose oxidation, GO). The suppression of GO in RVH is multifactorial,
reflecting direct inhibition of pyruvate dehydrogenase (PDH) by pyruvate dehydrogenase kinase
(PDK) and indirect inhibition of GO by fatty acid oxidation (FAO). FAO and GO have a reciprocal
relationship termed Randle’s cycle, such that inhibiting FAO increase GO. In RVH the RV (but not
the LV) relies on glycolysis and glutaminolysis, much like the metabolic phenotype in a cancer
cell. This leads to an energy depleted, hypokinetic RV. Using precise metabolic measurements in
cardiac myocytes and working heart) we assess the molecular basis of PDH activation in
complementary models of RVH that are either adaptive (PAB) or maladaptive (CH-SU, MCT). We
explore both molecular and pharmacologic interventions to increase GO by activating PDH
directly (DCA) versus indirectly via the Randle cycle using CPT1 inhibitors and MCD K/O mouse.
Hypothesis: PDH Inhibition in maladaptive RVH causes a glycolytic shift that impairs RV function.
Conversely activation of PDH, by PDK inhibition or Randle’s cycle (FAO inhibition) improves RV
function
Student project Determine the chamber specificity and physiologic importance of PDH
inhibition of adaptive vs maladaptive RVH RV metabolism and assess the response to
increasing glucose oxidation
Prerequisites:
1) Project suitable for a first of second year medical student provided they have a strong interest
in basic/translational research, some laboratory experience and willingness to use rodent
models of human diseases.
2) Must have read and be able to discuss the following publication: FOXO1-mediated
upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and
impairs right ventricular function in pulmonary hypertension: therapeutic benefits of
dichloroacetate. J Mol Med (Berl). 2013 Mar;91(3):333-46. doi: 10.1007/s00109-012-0982-0.
Funding source: NIH
Department: Department of Medicine
Investigator: Dr. Stephen Archer
Contact person: Ms. Clarrie Lam; clarrie.lam@queensu.ca
Summer Project 2: Mitochondrial fission in pulmonary hypertension:
Pulmonary arterial hypertension (PAH) is a disease of the lung’s blood vessels caused in part by
excessive rates of vascular growth, leading to vascular obstruction. This places a strain on the
right heart, causing disability and a 15% annual death rate due to right heart failure. We identified
a mitochondrial abnormality in human PAH smooth muscle cells that causes them to grow rapidly,
contributing to the blockage. In PAH the mitochondrial network is fragmented, a process called
“fission”. Excess fission reflects increased activity of an enzyme called dynamin related protein
(DRP-1). Inhibiting DRP-1 slows cell growth and reduces experimental PAH. We will define the
cause of increased fission in PAH and explore a link between fission and mitosis that relates to a
shared regulatory kinase, CDK1. Increased fission may present an Achilles heel for rapidly
growing cells. The therapeutic potential of anti-fission drugs is tested in human PAH tissues/cells
and in rodent models. This project is innovative in recognizing that “mitochondrial checkpoints”,
related to DRP-1 activation and fission, regulate cell cycle progression. The concept that
mitochondrial fission is tightly linked to cell cycle progression via shared regulatory kinases is also
novel. The discovery that inhibiting DRP-1 (directly or by targeting its regulatory kinases) is
antiproliferative offers a new, “antifission-profusion”, therapeutic paradigm for PAH. The
translational potential of this proposal is enhanced by careful correlation of results in rodent PAH
models with findings in human PAH lungs/cells from a well-characterized cohort.
Hypothesis: DRP-1 inhibition prevents cell cycle progression, causing G2-M phase arrest. Antifission therapies may constitute an antiproliferative therapy for PAH.
Student project: Determine whether inhibition of mitochondrial fission have therapeutic benefit
in experimental PAH? RVH RV metabolism and assess the response to increasing glucose
oxidation
Prerequisites:
1) Project suitable for a first of second year medical student provided they have a strong interest
in basic/translational research, some laboratory experience and willingness to use rodent
models of human diseases.
2) Must have read and be able to discuss the following publication: Mitochondrial Dynamics —
Mitochondrial Fission and Fusion in Human Diseases N Engl J Med 2013;369:2236-51.
Funding source: NIH
Department: Department of Medicine
Investigator: Dr. Stephen Archer
Contact person: Ms. Clarrie Lam; clarrie.lam@queensu.ca