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Genetic and Environmental Regulation of Diaphragm Development and Congenital Diaphragmatic Hernias

Award Number: R01HD104317
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Genetic and Environmental Regulation of Diaphragm Development and Congenital Diaphragmatic Hernias - The diaphragm is an essential mammalian skeletal muscle, as it is vital for respiration and serves as a barrier between the thoracic and abdominal cavities. Defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDHs), a common birth defect (1:3000 births) that results in severe morbidity and 50% mortality. Given the diaphragm's functional importance and the frequency and severity of CDH, an understanding of diaphragm development normally and during herniation is critical. Using mouse genetics, we definitively established that the pleuroperitoneal folds, transient embryonic structures, and the muscle connective tissue fibroblasts derived from them critically regulate development of the diaphragm muscle (Merrell et al. 2015). Furthermore, we showed that mutations in Gata4 in these fibroblasts cause CDH. Although conditional Gata4 mouse mutants have been critical for dissecting the role of PPFs and Gata4 in CDH, they are not representative of the genetic and phenotypic characteristics of CDH. We have identified and created new hypomorphic alleles of Gata4 that faithfully recapitulate both the genotypic and phenotypic characteristics of human CDH. Based on preliminary data with these new Gata4 alleles, we will test the hypothesis that Gata4 regulates in a dose-dependent manner development of development of the diaphragm and CDH. Genetic and environmental disruptions in retinoic acid (RA) signaling have also been proposed to be an important source of CDH. Using a series of mouse genetic alleles and protocols for modulating maternal vitamin A, we will explicitly test a role for RA and as well as RA and Gata4 interactions in diaphragm development and CDH. Our research will provide insights into the multifaceted genetic, molecular, cellular, and environmental mechanisms underlying the etiology of CDH and its phenotypic and clinical variability.


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 = $475,998 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	5	4/7/2025	NON-COMPETING CONTINUATION	$475,998
														Subtotal = $475,998

Issue Date FY: 2024 ( Subtotal = $471,238 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	4	4/12/2024	NON-COMPETING CONTINUATION	$428,398
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	001	4	5/23/2024	NON-COMPETING CONTINUATION	$42,840
														Subtotal = $471,238

Issue Date FY: 2023 ( Subtotal = $475,998 )
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	3	3/16/2023	NON-COMPETING CONTINUATION	$475,998
														Subtotal = $475,998

Issue Date FY: 2022 ( Subtotal = $479,910 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	2	5/9/2022	NON-COMPETING CONTINUATION	$479,910
														Subtotal = $479,910

Issue Date FY: 2021 ( Subtotal = $473,391 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	1	3/22/2021	NEW	$473,391
														Subtotal = $473,391

Grand Total All Awards = $2,376,535

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Genetic and Environmental Regulation of Diaphragm Development and Congenital Diaphragmatic Hernias

Award Number: R01HD104317

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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