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Serotonin Signaling in Mitral Valve Homeostasis, Maintenance and Restoration

Award Number: R01HL131872
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Serotonin Signaling in Mitral Valve Homeostasis, Maintenance and Restoration - Degenerative mitral regurgitation (MR) due to myxomatous valve disease affects millions. The only treatment is either valve repair or replacement. This competing renewal will advance understanding of the role of the neurotransmitter, serotonin (5HT) in MR. Heart valve disease has been associated with both 5HT-secreting carcinoid tumors and medications, such as the diet drug, Dexfenfluoramine. Based on our progress in the 1ST program period, we will investigate the hypothesis that 5HT-mechanisms involving the serotonin transporter (SERT), and 5HT receptor (HTR) signaling, both in platelets and mitral valve interstitial cells (MVIC) of bone marrow origin, contribute to the pathophysiology MR, and represent promising therapeutic targets. Specific Aim 1: To dissect 5HT-mediated mechanisms that influence pathologic remodeling of MV leaflets in human subjects and mice Subaim 1A: To characterize 5HT-mediated MV remodeling in MR compared to normal mitral valve (MV) leaflets and human-derived MVICs. SERT-antagonists, and HTR inhibitor studies will dissect unique 5HT related transcriptome and cellular phenotypes associated with MR progression in vitro and ex vivo under TGFβ, BMP4, and 5HT stimulation. Endpoints will be transcriptomic, extracellular matrix (ECM) remodeling in human MVIC and tissue from MR compared to normal leaflets exposed to 5HT-related mechanistic interrogation. Subaim 1B: To investigate the role of SERT in the pathogenesis of MR: The SERT deleted mouse (SERT-/-) spontaneously develops a valvulopathy affecting the mitral and aortic valves. Mechanistic studies will compare SERT-/- to SERT+/+ . Endpoints will include valve thickness, myocardial fibrosis, and changes in the MV transcriptome, to understand disease progression in this SERT-related valvulopathy. Specific Aim 2: To investigate the role of 5HT in the pathogenesis of MR involving platelet mechanisms and bone marrow derived blood outgrowth endothelial cells (BOEC) that express both CD34 and HTR2B. Subaim 2A: It is noteworthy that MR results in a chronic state of platelet activation, since platelets are the primary carriers of 5HT in blood, releasing 5HT upon activation. We will study the role of platelets in 5HT related MR pathophysiology in human subjects, canines with MR, and mice. Endpoints will include 5HT levels, platelet activation markers, and differences in TGF-b1 levels resulting from platelet alpha granule release. Subaim 2B: To investigate the role of bone marrow derived cells in the pathophysiology of 5HT mechanisms that affect MR. BOEC will be cultivated from the study groups in Subaim 2A. The experimental designs will use flow cytometry for cell characterization, qRT-PCR studies to assess gene expression patterns, and proteomic approaches to assess HTR activity, and measurements of ECM production in vitro. It is expected that the mechanistic results of these studies will lead to therapeutic directions for MR that target platelet derived 5HT and leverage a personalized approach using BOEC to model the pathophysiology.


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 = $790,183 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	9	7/23/2025	COMPETING CONTINUATION	$790,183
2025	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	002	8	7/30/2025	NON-COMPETING CONTINUATION	$0
2025	2023	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	7	4/7/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $790,183

Issue Date FY: 2024 ( Subtotal = $697,910 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	8	3/1/2024	NON-COMPETING CONTINUATION	$640,937
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	002	8	6/20/2024	NON-COMPETING CONTINUATION	$56,973
2024	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	7	10/17/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $697,910

Issue Date FY: 2023 ( Subtotal = $1,316,775 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	7	9/1/2023	SUPPLEMENT FOR EXPANSION	$594,951
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	7	1/30/2023	NON-COMPETING CONTINUATION	$721,824
														Subtotal = $1,316,775

Issue Date FY: 2022 ( Subtotal = $731,206 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	002	6	3/1/2022	NON-COMPETING CONTINUATION	$658,084
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	003	6	5/24/2022	NON-COMPETING CONTINUATION	$73,122
2022	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	5	2/23/2022	COMPETING CONTINUATION	$32,013
2022	2019	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	4	2/23/2022	NON-COMPETING CONTINUATION	-$32,013
														Subtotal = $731,206

Issue Date FY: 2021 ( Subtotal = $791,513 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	002	5	8/5/2021	COMPETING CONTINUATION	$0
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	5	3/1/2021	COMPETING CONTINUATION	$791,513
2021	2019	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	4	2/28/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $791,513

Issue Date FY: 2019 ( Subtotal = $648,985 )
2019	2019	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	4	4/9/2019	NON-COMPETING CONTINUATION	$648,985
														Subtotal = $648,985

Issue Date FY: 2018 ( Subtotal = $657,068 )
2018	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	3	3/19/2018	NON-COMPETING CONTINUATION	$643,926
2018	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	3	7/2/2018	NON-COMPETING CONTINUATION	$13,142
														Subtotal = $657,068

Issue Date FY: 2017 ( Subtotal = $664,532 )
2017	2017	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	2	3/31/2017	NON-COMPETING CONTINUATION	$664,532
														Subtotal = $664,532

Issue Date FY: 2016 ( Subtotal = $700,532 )
2016	2016	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	1	3/3/2016	NEW	$700,532
														Subtotal = $700,532

Grand Total All Awards = $6,998,704

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Serotonin Signaling in Mitral Valve Homeostasis, Maintenance and Restoration

Award Number: R01HL131872

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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