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Determining the effect of DNMT3A loss on the competitive fitness of mutant cells in somatic mosaicism

Award Number: F30HD111129
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/20/2022
PERIOD OF PERFORMANCE END DATE: 12/19/2026

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Determining the effect of DNMT3A loss on the competitive fitness of mutant cells in somatic mosaicism - PROJECT SUMMARY/ABSTRACT Epigenetic dysregulation is a shared mechanism of many developmental disorders. One such disorder, Tatton-Brown-Rahman Syndrome (TBRS), results from heterozygous mutations in the de novo DNA methyltransferase, DNMT3A. TBRS is characterized by intellectual disability, seizures, overgrowth, multiple developmental abnormalities, and a predisposition to various malignancies. Since its 2014 discovery, more than 200 patients with TBRS have been identified. In the blood, patients with TBRS exhibit decreased methylation at developmental gene clusters, and abnormal tissue development in patients with TBRS results in numerous lifelong complications. However, a major gap in knowledge is that the mechanism by which DNMT3A regulates development of non-hematopoietic tissues remains unknown. Our lab has identified two individuals who exhibit a mixture of wild-type and DNMT3A-mutant cells throughout their bodies, such that they are constitutive mosaics. The distribution of mutant cells is highly variable across their tissues, and concomitant analysis of wild-type and mutant cells reveals methylation differences that suggest a role of DNMT3A in tissue development. We hypothesize that DNMT3A wild-type and mutant cells have distinct propensities to form different tissues when directly competed with one another. Understanding which tissues are favored by mutant cells in somatic mosaics will lend insight into the pathogenesis of TBRS. To test our central hypothesis, I have established a novel mouse model of somatic mosaicism. I will use this mouse and an in vitro cell culture system to address two aims: 1) I will investigate the effect of Dnmt3a loss on the differentiation capacity of specific stem cell populations, and 2) I will investigate the downstream contribution of Dnmt3a-mutant versus wild-type cells to post-natal mouse tissues. Our long-term goal is to identify tissues in which DNMT3A loss confers a selective advantage or disadvantage and to explore the mechanism of this differential tissue composition. The project is designed to prepare me for a career as an academic pediatric oncologist specializing in inherited developmental and cancer predisposition syndromes. The Goodell lab has made seminal discoveries in DNMT3A biology and has a long track-record of successful MSTP trainees. The collaborative training environment at Baylor College of Medicine, with its state-of-the-art technology cores and prime location in the Texas Medical Center will facilitate the success of this project. In the future, the results of these studies may inform the clinical care of patients with TBRS by identifying tissues in which a DNMT3A mutation is poorly tolerated. The studies may also help to inform genetic counselling of parents of patients with TBRS about their risk of recurrence by characterizing expansion or depletion of DNMT3A-mutant cells in gonadal tissues. Finally, these results will expand our understanding of how mutant cells that appear in early embryogenesis compete with wild-type cells to shape normal and disordered development.


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 = $57,538 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	4	12/18/2025	NON-COMPETING CONTINUATION	$57,538
														Subtotal = $57,538

Issue Date FY: 2025 ( Subtotal = $55,601 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	3	11/29/2024	NON-COMPETING CONTINUATION	$52,037
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	002	3	6/24/2025	NON-COMPETING CONTINUATION	$564
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	001	3	4/23/2025	NON-COMPETING CONTINUATION	$3,000
														Subtotal = $55,601

Issue Date FY: 2024 ( Subtotal = $49,332 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	2	11/7/2023	NON-COMPETING CONTINUATION	$48,052
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	001	2	5/10/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $49,332

Issue Date FY: 2023 ( Subtotal = $47,110 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	001	1	12/20/2022	NEW	$0
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	1	12/20/2022	NEW	$47,110
														Subtotal = $47,110

Grand Total All Awards = $209,581

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Determining the effect of DNMT3A loss on the competitive fitness of mutant cells in somatic mosaicism

Award Number: F30HD111129

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/20/2022

PERIOD OF PERFORMANCE END DATE: 12/19/2026

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