Myocarditis Research
Presented by
Candace Moose
&
Dr. Leslie Cooper
Our Grant History
• The foundation will have awarded eleven
research fellowship grants by year end 2012.
• Each grant is awarded in the amount of
$30,000 to $35,000 dollars.
• They have been awarded to doctors in
University Hospitals across the US and in
Canada
Application Process
1. Applicants send their grant applications to the
foundation by December 1st.
2. The foundation’s Medical Advisory Board scores the
proposals and make a recommendation to the Board of
Directors as to which grants should be funded.
3. Applicants are notified and we begin negotiations on
their contracts.
4. When Contracts are signed, research begins on July 1st
through June 30th of the following year.
5. We receive updates on their research and maintain
contact even after their research has been completed
Application Overview
The MYOCARDITIS FOUNDATION (MF) awards funds to support research related to all forms of myocarditis research. The goal of MF’s research program is to
advance medical knowledge on the disease and develop more accurate diagnostic methods and life-saving therapies with the goal of saving more lives.
TYPES OF PROPOSALS SOUGHT
-The Myocarditis Foundation (MF) accepts fellowship grant applications on an annual basis for innovative basic, clinical or translational research relevant to the
cause or treatment of myocarditis. MF’s fellowship grant program is designed to provide seed funding to investigators for the testing of initial hypotheses and
collecting preliminary data to help secure long-term funding by the National Institute of Health (NIH) and other major granting institutions. Funding is available
at $35,000 USD for salary only.
-Grant award decisions are made through a peer review process by our Medical Advisory Board. Scientific excellence and relevance to myocarditis are the basic
criteria for selecting the supported research project. The award is designed to support training and career development of physician-scientists in myocarditis
research.
AVAILABLE FUNDING
The MF research grant provides salary support for 1 year of full-time research. The 2013-14 stipend is $35,000. No additional funds for benefits, travel, or
indirect costs, etc. are available.
ELIGIBILITY REQUIREMENTS
Candidates may apply up to 10 years following receipt of an MD, PhD, or an equivalent degree and plan to perform the funded work in the United States or
Canada, in order to apply for the Fellowship. All applicants must select a preceptor with a proven track record of research in myocarditis. In addition to
providing a letter of recommendation, the preceptor is expected to assist in preparing the application. For applicants wishing advice in the selection of a
preceptor, a list of potential preceptors is available from the MF.
APPLICATION PROCEDURE
The MF will issue one request for proposals in September 2012. The deadline for grant submission is December 1, 2012 with final award decisions made by
December 31, 2012. The research plan should be limited to 5 pages and must include the following: hypothesis, specific aims, background/significance,
preliminary data, methods and expected results. The applicant should include a cover letter, supporting letter from the preceptor, and applicant and preceptor
biographical sketches. Upon receipt of a signed letter of agreement from the selected candidate the MF will disburse the funds in installments during the
research year.
FINAL REPORT
A final report will be required upon completion of the research year. The Myocarditis Foundation reserves the right to cite the research in all/any of our printed
materials and on our website. The Myocarditis Foundation must be acknowledged in all publications resulting from the research.
Grant Recipients
Dr. David Marchant at
the University of
British Columbia in
Vancouver, Canada
Dr. Susan
Wollersheim at the
University of
California in Los
Angeles
Dr. Kevin Quinn at the
University of
California in Los
Angeles
Dr. Byung Kwan Lim
at the University of
California in San
Diego
Dr. Alan Valaperti at
the University of
Toronto in Canada
Dr. Laure Case at the
University of Vermont
in Burlington
Dr. Daniela Cihakova
at Johns Hopkins
University
Dr. Kathleen Simpson
at Washington
University
Dr. Silvio Antoniak at
University of North
Carolina in Chapel Hill
Dr. Bettina Heidecker
at the University of
Miami
2012-2013 Grant Recipients!
We are happy to announce this year’s grant recipients:
Dr. Laure Case
of the University of Vermont in Burlington
Department of Medicine
“Chromosome Y Regulates Susceptibility to Coxsackievirus B3-induced Myocarditis”
Dr. Kevin Quinn
of the University of California in Los Angeles
Department of Pediatrics
“Identifying Antiviral Agents to Treat Coxsackievirus Myocarditis”
Dr. Daniela Cihakova
of Johns Hopkins University
Awarded grant in 2007
“The Role of Monocytes in Autoimmune
Myocarditis
“We have assembled evidence that EAM is driven in part by the
Th17 pathway in the mouse; however, in the absence of IL-17A an
equally severe disease can be driven through the Th1 pathway. It is
not yet known whether IL-17 plays a similarly dominant role in the
pathogenesis of human myocarditis. Given a lack of
immunomodulatory treatments for myocarditis, blocking of the IL23/IL-17 pathway could be very attractive option. Thus, in
myocarditis different pathways can result in comparable disease
(Cihakova et al., 2008)’’
Dr. Bettina Heidecker
of the University of Miami
Awarded grant in 2007
“Gene Expression Profiling for Detection of
Myocarditis”
“The overall goal of this study is to improve diagnostic
sensitivity for detection of myocarditis by endomyocardial
biopsy derived transcriptomic biomarkers and to evaluate
peripheral blood mononuclear cells as possible surrogates of
heart tissue.”
Dr. Susan Wollersheim
of the University of California in Los Angeles
Awarded grant in 2008
“Cellular and Viral Determinants of Neonatal Group
B Coxsackievirus Myocarditis”
“Sequence comparisons of more recently circulating CVB1 and CVB3 virus 5’UTR and stemloop
2 folding patterns reveal that more recently circulating CVB1 and CVB3 viruses are more similar
to each other than to their prototype viruses from the 1940’s. The area of highest divergence
from protoype of each CVB was within the stemloop 2 structure, which has previously been
identified as a genomic determinant in CVB cardiovirulence [11]; this may indicate why the
newer strain of CVB1 was more cardiovirulent than ever described previously. This new CVB1Chi07 also has larger plaque size than CVB1-Conn5 which correlates with a higher viral
replication and titer [12]. The CVB1-Chi07 shows a slower rate of growth and lower peak titer
than all of the CVB3 viruses assessed. In vitro mouse models to compare these CVB1 viruses
have been initiated with one experiment which indicates that CVB1-Chi07 is much more virulent
than CVB1-Conn5, however further studies and data will be collected to verify this.
IRES transactivating protein identification is preliminary at this time, but the three proteins that
have been identified are involved in cellular translation. Further studies of confirmation are
underway and future experiments will be performed with mouse myocyte proteins.”
Dr. Silvio Antoniak
of the University of North Carolina in Chapel Hill
Awarded grant in 2009
“Thrombin-PAR-1 Signaling in Viral Myocarditis”
“I conclude that PAR-1 activation is essential in the early phase of virus
infection to manage an effective immune response against CVB3. This
response is maintained by a successful recognition of virus’ antigens by
the TLR-3 pathway and a PAR-1 dependent NK cell activation. The altered
immune reaction in PAR-1-/- mice leads to uncontrolled virus replication
and later to an over-bursting immune response, aberrant cardiac
remodeling leading to cardiac dysfunction after CVB3 infection.”
Dr. David Marchant
of the University of British Columbia
in Vancouver, Canada
Awarded grant in 2009
“Discovering and Understanding Virus-Host Factor
Interactions for Treatment of Viral Myocarditis”
“We showed that virus signaling during infection originated from, and
converge upon, dominant signaling ‘nodes.” This work, which employed
several signaling inhibitors to investigate signaling ‘networks,” identified
those target whose inhibition most effectively inhibited viral replication;
the ‘nodes.’ We concluded that by targeting the dominant signaling
nodes that are required for viral replication we could, hypothetically,
discover the most effective target for treatment of CVB3 infection. This is
the first work of its kind and should provide new avenues for investigation
of the most effective antivirals for treatment of virally induced
myocarditis.”
Dr. Byung Kwan Lim
of the University of California in San Diego
Awarded grant in 2009
“The Role of Dystrphin in Enterovirus Induced Viral
Myocarditis”
Specific Aim1. Determine whether cardiac myocyte-specific, inducible expression of enterovirus protease 2A in the
dystrophin knock-in adult mouse heart can prevent myocyte sarcolemmal membrane disruption and the
subsequent development of cardiomyopathy.
Hypothesis: Dystrophin knock-in can prevent mycoyte sarcolemmal membrane disruption through inhibition of
dystrophin cleavage by enterovirus protease 2A.
Expected Results: We will generate DysKI/2A/MCM triple transgenic mice to determine the effect of cleavageresistant dystrophin in cardiac-specific inducible expression of enterovirus protease 2A.
Specific Aim2. Determine whether knock-in of dystrophin that prevent protease 2A cleavage of dystrophin can
protect against CVB3 infection mediated cardiac myocyte damage and myocarditis.
Hypothesis: Dystrophin knock-in reduces dystrophin cleavage and sarcolemmal membrane disruption after CVB3
infection.
Expected Results: We generated inbred Balb/C DysKI mice to determine whether DysKI mice have less
sarcolemmal membrane disruption and myocyte damage in CVB3 infection. Preliminary data showed no
significant difference between DysKI and littermate controls. There are similar virus titer and Evans blue dye
uptake percent. However, Balb/C mice have high susceptibility to CVB3 and immune response. To prove a
mechanical effect of virus infection we will generate less susceptible inbred C3H background DysKI mice.
Dr. Kathleen Simpson
of Washington University in St. Louis, MO
Awarded grant in 2010
“Autoimmunity in Pediatric Myocarditis:
A Pilot Study”
“The relationship of autoimmunity in the pathophysiology and outcomes
of pediatric myocarditis is unknown. Through the collaboration of regional
pediatric hospitals encompassing the states of Missouri, Oklahoma, and
Nebraska, we plan to determine the relationship of autoimmunity to
outcomes in previously and newly diagnosed pediatric myocarditis. In
addition, we will use MRI of the heart to determine specific findings in
children and the role of MRI in disease progression and prognosis for
children with myocarditis. Improving the understanding of patient immune
reaction in myocarditis may lead to improvement in prognosis and
treatment in children.”
Dr. Alan Valaperti
of the University of Health Network
at the University of Toronto in Canada
Awarded grant in 2011
“IL-1 Receptor-associated Kinase 4 (IRAK4) Epigentically
Modulates Nod2- and MDA5- dependent Protection in Viral
Myocarditis”
“First we observed that the major cell population infiltrating into the inflamed heart of Coxsackie virus B3 (CVB3)inoculated IRAK4 deficient mice were macrophages. We were able to show that upon in vitro infection with
Coxackievirus B3 (CVB3), IRAK4 down-regulated IFN-α and IFN-γ, but not IFN-β, exclusively in macrophages, but not in
myeloid dendritic cells or plasmacytoid dendritic cells. Simultaneous down-regulation of IFN-α and IFN-γ, which
means up-regulation of IFN-α and IFN-γ in IRAK4 deficient cells, was enough to dramatically reduce viral replication in
infected macrophages.”
“In addition, IRAK4 showed unique functions that were only partially shared with its upstream molecule MyD88. In
particular, IRAK4 deficiency showed better stability of MDA5, which is an important cytoplasmic receptor to recognize
Coxackievirus genome to mount an interferon-dependent anti-viral response. On the contrary, CVB3-infected wildtype macrophages showed a relevant degradation of MDA5 few hours after infection, whereas MyD88 deficient cells
showed degradation of MDA5 in a later stage. This resulted in higher viral protection in IRAK4 deficient cells compared
to wild-type or MyD88 deficient counterparts.”
Dr. Laure Case
of the University of Vermont
Awarded grant in 2012
“Chromosome Y Regulates usceptibility to
Coxsackievirus B3-induced Myocardtis”
“The experiments proposed in this fellowship will identify the critical cell types, for
example cardiomyocytes and/or immune cells, which influence myocarditis susceptibility
in the consomic mice. Thisdata will provide the necessary cellular link for future work
that tests the hypothesis that ChrY dependent regulation of genes on other
chromosomes is evolutionarily conserved, and that this mechanism influences
myocarditis susceptibility among male mice. This is a very novel and exciting area of
genetic research that will reveal ChrY’s contribution to phenotypic differences that
directly impact susceptibility to myocarditis and allow for the identification of genes and
pathways that can be targeted for mechanistic studies and therapeutic intervention.”
Dr. Kevin Quinn
of the University of California in Los Angeles
Awarded grant in 2012
“Identifying Antiviral Agents to Treat Coxsackievirus
Myocarditis”
“In support of a long-term goal of identifying potent and tolerable antiviral drugs to
prevent enteroviral myocarditis, our project has the following 3 goals:
1) To identify the compounds which most actively inhibit coxsackievirus replication in
tissue culture cells
2) To identify the mechanism of action that allows these viral inhibitors to prevent
coxsackievirus from completing its lytic cycle
3) To test the most active inhibitors in a mouse model of coxsackievirus myocarditis.
Those effective in inhibiting coxsackievirus infection in animal models could in turn be
evaluated towards application in human patients.”
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