Monday, May 19, 2025 5/19/2025

Mechanistic Insights into The Role of Microtubule Organizing Centers on Cardiomyocyte Structure and Function

Award Number: R01HL167133
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Mechanistic Insights into The Role of Microtubule Organizing Centers on Cardiomyocyte Structure and Function - In comparison to the advances in the medical treatment of adult heart failure over the past 50 years, relatively little progress has been made in the treatment of pediatric dilated cardiomyopathies (DCM). While the majority of pediatric DCM cases are considered idiopathic, genetic etiologies are commonly suspected. Pediatric DCM has a poor prognosis, particularly for infants < 1-year-old. Drug development efforts for pediatric heart failure have been hampered by the lack of understanding of disease pathophysiology. Against this backdrop, our lab recently identified the RTTN gene, encoding the centrosome protein Rotatin, as a new causal gene for nonsyndromic congenital dilated cardiomyopathy (cDCM). Additionally, we found that impaired cardiomyocyte maturation, involving the failure to assemble perinuclear microtubule organizing center (pnMTOC), underlies the structural and functional defects observed in the mutant cardiomyocytes. Based on this finding, we hypothesize that impaired postnatal cardiomyocyte maturation, in which the primary MTOC fails to switch from the centrosome to the perinuclear region, is a new general paradigm for the pathogenesis of cDCM. Remarkably, we found that a small molecule C19 can restore cardiomyocyte maturation and reverse every feature of cDCM, including impaired pnMTOC assembly, in the induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model. To better understand the composition and the functional role of pnMTOC important for proper sarcomere alignment during cardiomyocyte maturation, we will utilize the following specific aims: 1) Determine which centrosome proteins are dependent on RTTN for perinuclear relocalization during cardiomyocyte maturation; 2) Determine which centrosome proteins play a functional role in MT cytoskeleton assembly and sarcomere alignment in mature cardiomyocytes, and 3) Elucidate the mechanism by which C19 rescues pnMTOC assembly in RTTN-/- cardiomyocytes. The proposed research is highly innovative in that it leverages the newly discovered insights to cDCM pathogenesis to develop future precision medicines with a transformational impact on the lives of infants with this devastating illness.


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 = $518,486 )
2025	2025	HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Cardiovascular Diseases Research	000	3	5/14/2025	NON-COMPETING CONTINUATION	$518,486
														Subtotal = $518,486

Issue Date FY: 2024 ( Subtotal = $510,145 )
2024	2024	HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Cardiovascular Diseases Research	002	2	6/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$43,510
2024	2024	HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Cardiovascular Diseases Research	001	2	4/16/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$466,635
2024	2024	HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Cardiovascular Diseases Research	004	2	7/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$452,185
2024	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	003	1	7/15/2024	NEW	-$452,185
2024	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	1	4/12/2024	NEW	$0
														Subtotal = $510,145

Issue Date FY: 2023 ( Subtotal = $510,230 )
2023	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	1	6/15/2023	NEW	$510,230
														Subtotal = $510,230

Grand Total All Awards = $1,538,861

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Mechanistic Insights into The Role of Microtubule Organizing Centers on Cardiomyocyte Structure and Function

Award Number: R01HL167133

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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