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Chromatin remodeling factor CHD7 regulates cardiac and craniofacial lymphatic vessel development

Award Number: R01HL176018
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/25/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Chromatin remodeling factor CHD7 regulates cardiac and craniofacial lymphatic vessel development - Project Summary The anterior second heart ﬁeld (SHF) cells are a population of late differentiating cardiovascular progenitor cells that contribute to myocardial cells, smooth muscle cells, and endothelial cells in the heart. It was not discovered until recently that these SHF progenitors can also contribute to cardiac lymphatic endothelial cells (LECs) as well as the lymphatics of the craniofacial area in mice. Lymphatics play essential roles in regulating interstitial fluid homeostasis and immune cell modulation. It is unclear whether lymphatic defects can cause congenital cardiac and craniofacial malformations. Mutation in CHD7, a gene encoding Chromodomain Helicase DNA Binding Protein 7 that functions as an ATP-dependent chromatin remodeler, cause craniofacial defects and cardiovascular malformations. It has been reported that CHD7 plays a cell-autonomous role in SHF progenitors to regulate downstream gene expression. Our preliminary data further demonstrated that CHD7 is highly expressed in cardiac lymphatic progenitors and chd7 mutant zebrafish show defects in lymphatics in the craniofacial areas, on the out flow tract and the heart ventricle. We will test the hypothesis that CHD7 regulates gene expression and chromatin accessibility in cardiac and craniofacial LECs derived from SHF progenitors. We propose two independent aims to 1) perform confocal and live imaging and lineage tracing to analyze the chd7 mutant phenotypes and SHF contributions to craniofacial and cardiac LECs; 2) perform single nuclei Multiomic amalysis, spatial transcriptomics and CUT&RUN to determine the molecular mechanisms by which CHD7 regulates downstream gene expression and chromatin landscapes. Our proposed experiments will reveal previously unappreciated roles of CHD7 in LECs derived from SHF progenitors and help identify CHD7 downstream target genes that can be potential therapeutic targets for patients with CHD and lymphatic malformations.


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 = $612,059 )
2025	2025	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	4/21/2025	NON-COMPETING CONTINUATION	$612,059
														Subtotal = $612,059

Issue Date FY: 2024 ( Subtotal = $737,809 )
2024	2024	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	7/25/2024	NEW	$737,809
														Subtotal = $737,809

Grand Total All Awards = $1,349,868

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Chromatin remodeling factor CHD7 regulates cardiac and craniofacial lymphatic vessel development

Award Number: R01HL176018

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/25/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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