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Cardiac fibroblast MHCII contribution to cardiac pathophysiology in Doxorubicin cardiomyopathy

Award Number: F31HL175911
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Cardiac fibroblast MHCII contribution to cardiac pathophysiology in Doxorubicin cardiomyopathy - PROJECT SUMMARY Cancer patients receiving Doxorubicin (Dox) chemotherapy often develop cardiac complications which can result in heart failure (HF). Some of the prominent hallmarks of Dox HF patients are cardiac fibrosis, cardiac atrophy, systolic dysfunction as well as heightened systemic inflammation. Cardiac fibrosis and cardiac inflammation often coincide in nearly all forms of HF, and while the concept that cardiac fibroblasts, a heterogeneous and plastic cell type in response to stressors, and immune cells communicating with each other to exert cardiac pro-fibrotic and pro-inflammatory responses is emerging, it remains incompletely understood, and the immune and fibrotic mechanisms involved in Dox HF are understudied. My lab previously reported that one way of communicating is that cardiac fibroblasts can function as antigen presenting cells through the major histocompatibility complex class II (MHC-II), which is induced by IFN-γ, and my preliminary data using a mouse model of Dox cardiomyopathy demonstrate increased expression of MHC-II on a subset of cardiac fibroblast, coinciding with increased infiltration of IFNγ+ T cell subsets and cardiac fibrosis. My data also demonstrate that MHC-II induction on cardiac fibroblasts is T cell dependent and that specific deletion of cardiac fibroblast MHC-II in mice results in preserved systolic function and decreased fibrosis. In two aims I will test the central hypothesis that Dox induces a pro-inflammatory cardiac fibroblast state characterized by MHC-II expression through T cell IFN-γ signals that contribute to cardiac fibrosis and pathophysiology. In SA1, I will investigate the mechanisms by which MHC-II on cardiac fibroblasts contribute to T cell immune responses and cardiac fibrosis during the progression of Dox cardiomyopathy. In SA2, I will interrogate whether cardiac fibroblast MHC-II expression dictates fibroblast function and crosstalk with T cells in Dox cardiomyopathy. I will combine in vitro and in vivo gain and loss of function approaches. Overall, my project will identify novel mechanisms in the fibroblast-T cell interface that may be targeted to ameliorate Dox cardiomyopathy, while supporting my PhD training.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $45,726 )
2026	2026	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	3/2/2026	NON-COMPETING CONTINUATION	$45,726
														Subtotal = $45,726

Issue Date FY: 2024 ( Subtotal = $45,162 )
2024	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	7/25/2024	NEW	$45,162
														Subtotal = $45,162

Grand Total All Awards = $90,888

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Cardiac fibroblast MHCII contribution to cardiac pathophysiology in Doxorubicin cardiomyopathy

Award Number: F31HL175911

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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