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Admin Supplement: Epigenetic Determinants of Competence for Germ Line Specification during Cynomolgus Embryonic Development

Award Number: K08HD098556
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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Project Summary CANDIDATE. I am a physician and Instructor in the Division of Reproductive Endocrinology and Infertility at Beth Israel Deaconess Medical Center (BIDMC). A K08 Award will provide me with the necessary training and experience to become an independent investigator in germ cell (GC) biology, with a focus on the gene regulatory networks underlying human gametogenesis. BACKGROUND. How a small subset of cells in the developing human embryo acquires competency to form the germ line and ultimately mature into functional gametes while maintaining its potential for pluripotency is among the least understood questions in biology. In particular, the gene regulatory networks and epigenetic remodeling, which govern competence for the GC fate during specification of early (primordial) germ cells (PGCs) in the peri-gastrulating period, remain unknown. Knowledge of the underlying mechanisms will allow the development of more efficient differentiation protocols for GCs from pluripotent stem cells (PSCs) in vitro. In addition, it will allow the investigation of the link between epigenetic dysregulation during GC specification and critical human disorders such as pregnancy loss, congenital defects and common late-onset diseases such as infertility, diabetes, drug addiction and cancer. RESEARCH. The objective for this K08 is to identify and validate the key gene regulatory elements (GREs) governing induction of competence for the GC fate and the differentiation of PGCs during human gastrulation. Our central hypothesis is that epigenetic priming of key GREs in incipient mesoderm mediates developmental competence during germ lineage specification from the pluripotent state. This research will pursue two specific aims: (1) to identify putative GREs underlying developmental competence for the GC fate through epigenetic footprinting (2) to identify the subset of these GREs functioning as key determinants of GC competence and differentiation using massively parallel reporter assays (MPRA) and CRISPR epigenome editing mediated loss of function experiments. In the future, these results will provide the platform to use epigenome editing as a tool to improve the efficiency of GC specification, for trans-differentiation of GCs from somatic cells and to study the effect of epimutations on developmental outcomes in GCs and embryos using animal models. MENTORING. My primary mentor, Dr. Raymond Anchan, is an expert in stem cell biology at Brigham and Women’s Hospital. I have assembled a multi-disciplinary mentoring team across the Harvard network: Dr. Alex Meissner (an expert in epigenetics and epigenomics), Dr. Steve McCarroll (a leader in genomics and bioinformatics). TRAINING. The research objectives are supported by a training plan that includes laboratory training as well as rigorous formal didactics in genomics, bioinformatics, epigenetics and developmental biology alongside a strong institutional commitment at BIDMC and the grant review and support program through Harvard Catalyst.


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: 2024 ( Subtotal = $164,860 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	5	4/5/2024	NON-COMPETING CONTINUATION	$164,860
2024	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	3	4/24/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $164,860

Issue Date FY: 2023 ( Subtotal = $218,860 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	4	4/26/2023	NON-COMPETING CONTINUATION	$164,860
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	3	2/15/2023	SUPPLEMENT FOR EXPANSION	$54,000
														Subtotal = $218,860

Issue Date FY: 2022 ( Subtotal = $164,860 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	3	5/3/2022	NON-COMPETING CONTINUATION	$164,860
														Subtotal = $164,860

Issue Date FY: 2021 ( Subtotal = $164,860 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	2	3/12/2021	NON-COMPETING CONTINUATION	$164,860
														Subtotal = $164,860

Issue Date FY: 2020 ( Subtotal = $166,860 )
2020	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	1	4/21/2020	NEW	$166,860
														Subtotal = $166,860

Grand Total All Awards = $880,300

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Admin Supplement: Epigenetic Determinants of Competence for Germ Line Specification during Cynomolgus Embryonic Development

Award Number: K08HD098556

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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