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Transcriptional regulation of mesoderm development

Award Number: R15DE018519
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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Transcriptional regulation of mesoderm development - PROJECT SUMMARY Transcription factors play an important role in tissue-specific gene regulation during development. The basic helix-loop-helix (bHLH) transcription factors TWIST1 and TWIST2 are critical regulators of cell fate and differentiation during vertebrate development. These factors are mutated in several diseases that lead to craniofacial, digit, and other defects making it important to understand how these bHLH factors function and the underlying causes associated with their disease phenotypes. bHLH proteins form dimers with their HLH domains and bind to DNA sequences called E boxes with the basic DNA binding domains of the dimer partners. Although much is known about DNA binding and dimer formation, very little is known about the cooperation between the two domains for proper bHLH function. A glutamic acid in the DNA binding domain is predicted to play a critical role based on three pieces of evidence. There is a lack of amino acid variation at that position in bHLH protein alignments, bHLH crystal structures predict the glutamic acid makes direct contacts with DNA, and patients with amino acid substitutions in either TWIST1 or TWIST2 in that residue have disease phenotypes. The experiments in this proposal are designed to test the hypothesis that missense mutations of the conserved glutamic acid residue in the Twist DNA binding domain alter E-box regulated transcription due to disrupted protein-protein interactions. The simple nematode, Caenorhabditis elegans, is an excellent model genetic system for elucidating Twist function because the organism contains only one Twist-related protein, HLH-8, and HLH-8’s partner protein and downstream target genes are conserved with human TWIST1. Even though this organism is an invertebrate and can’t have craniofacial or digit defects, the conserved Twist pathway suggests that aspects of the cellular mechanisms will be conserved as well. In Aim 1, missense mutations in HLH-8 that mimic human disease alleles in the conserved glutamic acid will be characterized in C. elegans. The goal will be to understand the specific cellular defects of the mutants. Preliminary studies indicate that some of the mutants can still bind DNA to turn on target genes. These mutants will be the focus of the research in the second aim. In Aim 2, the C. elegans mutants will be used in modifier genetic screens designed to identify new proteins that cooperate with HLH-8 and, by analogy, may be potential therapeutic targets for Twist-related human diseases. The projects in the proposed work are suitable for students so the research will have a profound impact on the education of undergraduate and graduate students. The broad goal of this research is to elucidate HLH-8 function and target gene regulation. Due to the relatedness between the human and C. elegans Twist proteins, information learned will be relevant to understanding human TWIST1 and TWIST2 and disease pathology.


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: 2023 ( Subtotal = -$12,280 )
2023	2017	CATHOLIC UNIVERSITY OF AMERICA (THE)	620 MICHIGAN AVE NE	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Oral Diseases and Disorders Research	000	2	10/1/2022	COMPETING CONTINUATION	-$12,280
														Subtotal = -$12,280

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2017	CATHOLIC UNIVERSITY OF AMERICA (THE)	620 MICHIGAN AVE NE	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Oral Diseases and Disorders Research	000	2	8/23/2021	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2017	CATHOLIC UNIVERSITY OF AMERICA (THE)	620 MICHIGAN AVE NE	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Oral Diseases and Disorders Research	000	2	8/25/2020	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $441,883 )
2017	2017	CATHOLIC UNIVERSITY OF AMERICA (THE)	620 MICHIGAN AVE NE	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Oral Diseases and Disorders Research	001	2	9/20/2017	COMPETING CONTINUATION	$0
2017	2017	CATHOLIC UNIVERSITY OF AMERICA (THE)	620 MICHIGAN AVE NE	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Oral Diseases and Disorders Research	000	2	9/5/2017	COMPETING CONTINUATION	$441,883
														Subtotal = $441,883

Issue Date FY: 2010 ( Subtotal = $0 )
2010	2007	CATHOLIC UNIVERSITY OF AMERICA	620 MICHIGAN AVE. N. E.	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Oral Diseases and Disorders Research	000	1	9/17/2010	NEW	$0
														Subtotal = $0

Issue Date FY: 2007 ( Subtotal = $202,080 )
2007	2007	CATHOLIC UNIVERSITY OF AMERICA	620 MICHIGAN AVE. N. E.	WASHINGTON	DC	20064	DISTRICT OF COLUMBIA	USA	Oral Diseases and Disorders Research	000	1	8/3/2007	NEW	$202,080
														Subtotal = $202,080

Grand Total All Awards = $631,683

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Transcriptional regulation of mesoderm development

Award Number: R15DE018519

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/05/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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