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The Role of Platelet-Derived Transforming Growth Factor Beta in Abdominal Aortic Aneurysm

Award Number: F31HL175976
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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The Role of Platelet-Derived Transforming Growth Factor Beta in Abdominal Aortic Aneurysm - PROJECT SUMMARY/ABSTRACT Abdominal Aortic Aneurysm (AAA) is the 15th leading cause of death in the United States with a ruptured aneurysm resulting in an 80% likelihood of mortality. AAAs are typically diagnosed as an incidental finding and managed via follow-up imaging modalities to track aneurysm size and growth rate. If the aneurysm reaches a critical diameter of 5.5 cm in men or 5.0 cm in women, a surgical repair is recommended. Despite numerous promising preclinical studies, all medical therapies have failed to attenuate the progression of established AAAs in patients. This situation creates a serious gap in therapeutic aneurysm care as a significant number of patients suffer a fatal rupture before surgical repair. Our failure to identify an effective therapeutic is likely due to our poor understanding of the molecular mechanisms influencing AAA initiation and progression. Transforming growth factor β1 (TGFβ1) is a ubiquitously expressed cytokine initiating complex signaling pathways that influence cell proliferation, differentiation, and inflammation. Researchers have shown that TGFβ1 is a crucial mediator of aortic homeostasis. Antibody-mediated targeting of TGFβ1 has resulted in consistent worsening of AAA in multiple rodent models while overexpression of TGFβ1 attenuated aneurysm progression. These studies provide strong evidence for TGFβ1 playing a protective role, however the source and mechanism of protective TGFβ1 remains unknown. We need to understand how this key signaling pathway is affecting this disease to develop a clearer picture of AAA progression. The primary goal of this proposal is to evaluate platelets as a source of protective TGFβ1 and aortic adventitial fibroblasts as the mediating cell type. Thus, we hypothesize that platelet-derived TGFβ1 mitigates pathologic aortic expansion by binding to adventitial fibroblasts, stimulating extracellular matrix formation, and reinforcing the aortic wall. Our two specific aims will (1) evaluate platelet-specific depletion of TGFβ1 in multiple models of murine AAA and (2) assess adventitial fibroblasts as the mediator of protective TGFβ1 signaling. Successful completion of this F31 proposal will increase our understanding of the mechanisms by which TGFβ signaling protects AAA initiation and progression and may generate new avenues of research directed towards therapies for AAA patients. The experience gained from completing this proposal under the mentorship of Dr. Owens and my thesis committee at the University of Cincinnati will facilitate my growth into an independent investigator.


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: 2025 ( Subtotal = $49,524 )
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	000	2	8/13/2025	NON-COMPETING CONTINUATION	$49,524
														Subtotal = $49,524

Issue Date FY: 2024 ( Subtotal = $48,960 )
2024	2024	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	000	1	8/20/2024	NEW	$48,960
2024	2024	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	001	1	8/20/2024	NEW	$0
														Subtotal = $48,960

Grand Total All Awards = $98,484

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The Role of Platelet-Derived Transforming Growth Factor Beta in Abdominal Aortic Aneurysm

Award Number: F31HL175976

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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