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Dissecting the Molecular Role of TBX1 in the Context of Human Pharyngeal EndodermDevelopment

Award Number: R01HL157139
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Dissecting the Molecular Role of TBX1 in the Context of Human Pharyngeal EndodermDevelopment - PROJECT SUMMARY 22q11.2 Deletion Syndrome (22q11.2DS), the most common of the microdeletion syndromes, is caused by hemizygous loss of 0.7-3 Mb of DNA on chromosome 22 and results in a constellation of clinical phenotypes. The core phenotype originates from disrupted development of the pharyngeal apparatus. Particularly affected are the second heart field-dependent heart structures, great vessels, parathyroids, thymus, and lower craniofacial and face muscles. Although approximately 50 genes may be deleted, it is the haploinsufficiency of the transcription factor TBX1 that recapitulates most of the critical phenotype associated with 22q11.2DS. Genetic and developmental mouse studies have established that TBX1 is critical for typical development of the pharyngeal endoderm, a transient anatomical structure necessary for development of the thymus, parathyroids, and 4th pharyngeal arch arteries. Despite this central role, very little is known regarding the molecular mechanisms by which TBX1 functions in the pharyngeal endoderm. While a handful of studies have attempted to study the role of TBX1 in human cells, the cell types they have been conducted in are not representative of the appropriate developmental stage where and when TBX1 plays its critical role. To date, an effort to integrate all the critical genes into a pharyngeal endoderm or 4th pharyngeal arch arteries network has not been attempted, particularly in human cells. This R01 leverages recent development of an in vitro model which faithfully mimics the formation and progression of human pharyngeal endoderm, thereby providing an unprecedented opportunity to tease out the functions of TBX1 in its physiological context. Specifically, this model will be used to identify the transcriptional targets and partners of TBX1 (Aim1), investigate the role of TBX1 as epigenetic regulator of the human pharyngeal endoderm (Aim2), and mechanistically investigate newly discovered putative regulatory regions of the TBX1 locus (Aim3). The overarching hypothesis is that TBX1 is at the center of a Gene Regulatory Network critical for both the formation and maturation of the pharyngeal endoderm and the morpho-patterning of the surrounding mesoderm and neural crest cells. The proposed work is expected to identify the molecular mechanism at the basis of TBX1 haploinsufficiency and identify pathways which could be rescued through pharmacological intervention. Dissection of the epigenetic and molecular machinery responsible for pharyngeal endoderm formation will be instrumental in informing the generation of cell therapies for 22q11.2DS.


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: 2026 ( Subtotal = $392,500 )
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Lung Diseases Research	001	5	5/8/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$392,500
2026	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	4	4/30/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,500

Issue Date FY: 2025 ( Subtotal = $393,500 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	4	4/29/2025	NON-COMPETING CONTINUATION	$393,500
														Subtotal = $393,500

Issue Date FY: 2024 ( Subtotal = $393,500 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	3	4/30/2024	NON-COMPETING CONTINUATION	$393,500
														Subtotal = $393,500

Issue Date FY: 2023 ( Subtotal = $393,500 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	2	4/17/2023	NON-COMPETING CONTINUATION	$393,500
														Subtotal = $393,500

Issue Date FY: 2022 ( Subtotal = $393,500 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	001	1	7/20/2022	NEW	$0
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	1	4/28/2022	NEW	$393,500
														Subtotal = $393,500

Grand Total All Awards = $1,966,500

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Dissecting the Molecular Role of TBX1 in the Context of Human Pharyngeal EndodermDevelopment

Award Number: R01HL157139

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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