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Cardiac Fibroblasts in Postnatal Development and Adult Injury Response

Award Number: R01HL142217
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Cardiac Fibroblasts in Postnatal Development and Adult Injury Response - Abstract The cardiac fibroblast and its ability to convert into a myofibroblast for extracellular matrix (ECM) production, ventricular remodeling and the fibrotic response has been an area of recent investigation with important medical relevance. Here, a dual-PI renewal resubmission application is proposed by a developmental cardiac biologist and adult disease-based cardiac biologist to address how the postnatal heart matures in adulthood and then transitions back to a fetal-like program with disease stimulation through direct paracrine crosstalk and ECM feedback. During the past funding cycle of this award, we identified key regulatory relationships that exist between myocytes and fibroblasts in both the developing and diseased adult heart, whereby the ECM and transforming growth factor-β (TGFβ) served as an integrating platform between these 2 cell-types. We have also observed that fibroblast-expressed GDF10 and the epidermal growth factor (EGF) family member pleiotrophin (Ptn) mediate critical crosstalk between fibroblasts and myocytes. Here, we will investigate the hypothesis that TGFβ is a myocyte selective maturation factor that controls fibroblast activity in generating an effective ECM within the postnatal heart that also underlies adult disease, and that parallel Ptn and GDF10 signaling crosstalk further regulates fibroblast proliferation and promotes cardiomyocyte hypertrophy in development and disease. The dual-PI renewal application has 3 specific aims: 1) To examine how cardiomyocyte generated TGFβ1/2/3 and its subsequent signaling to cardiac fibroblasts underlie ECM neonatal maturation and adult ventricular remodeling, 2) To examine how cardiac fibroblast generated ECM regulates developmental cardiomyocyte maturation and adult heart remodeling, in part through TGFβ1/2/3 sequestration/release, and 3) To examine the function of the cardiac fibroblast-secreted growth factors Ptn and GDF10 in postnatal heart development and adult injury. Collectively, these specific aims will uncover novel signaling mechanisms that underlie heart maturation just after birth and determine how these mechanisms are redeployed in disease. Thus, the impact of this program will be the identification of novel signaling mechanisms and effectors that can be therapeutically targeted in human heart disease to positively effect cardiac remodeling and longstanding fibrosis, with added implications for treating congenital malformations and developmental growth abnormalities.


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 = $785,229 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	002	7	7/2/2025	NON-COMPETING CONTINUATION	$785,229
2025	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	001	5	1/30/2025	COMPETING CONTINUATION	$10,121
2025	2021	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	4	1/30/2025	NON-COMPETING CONTINUATION	-$10,121
														Subtotal = $785,229

Issue Date FY: 2024 ( Subtotal = $778,115 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	6	2/15/2024	NON-COMPETING CONTINUATION	$714,596
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	001	6	6/22/2024	NON-COMPETING CONTINUATION	$63,519
														Subtotal = $778,115

Issue Date FY: 2023 ( Subtotal = $802,498 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	001	5	3/15/2023	COMPETING CONTINUATION	$802,498
2023	2021	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	4	3/9/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $802,498

Issue Date FY: 2021 ( Subtotal = $687,175 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	4	6/28/2021	NON-COMPETING CONTINUATION	$687,175
														Subtotal = $687,175

Issue Date FY: 2020 ( Subtotal = $694,633 )
2020	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	3	7/15/2020	NON-COMPETING CONTINUATION	$694,633
														Subtotal = $694,633

Issue Date FY: 2019 ( Subtotal = $701,873 )
2019	2019	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	2	6/8/2019	NON-COMPETING CONTINUATION	$701,873
														Subtotal = $701,873

Issue Date FY: 2018 ( Subtotal = $708,905 )
2018	2018	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	1	6/15/2018	NEW	$708,905
														Subtotal = $708,905

Grand Total All Awards = $5,158,428

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Cardiac Fibroblasts in Postnatal Development and Adult Injury Response

Award Number: R01HL142217

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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