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The Role and Regulation of TRP53 Activity in Oocytes and Granulosa Cells After Radiation-induced Damage

Award Number: F31HD108973
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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The Role and Regulation of TRP53 Activity in Oocytes and Granulosa Cells After Radiation-induced Damage - Project Summary Ionizing radiation (IR) is a treatment used against cancer and to ablate patient's bone marrow prior to hematopoietic stem cell transplantation. IR induces damage (double strand breaks or reactive oxygen species) in target cells but can also kill healthy bystander cells. Primordial follicles (PFs) are a limited population of ovarian follicles that contain immature oocytes and are highly susceptible to damage. Damage induced by IR or other genotoxic chemotherapies can deplete the ovary of PFs resulting in premature ovarian insufficiency (POI) and infertility. Therefore, there is a need to understand how damage affects ovarian cells and leads to POI before less toxic therapeutic or predictive treatments can be developed. The goal of this project is to determine the mechanism of radiation-induced oocyte elimination in mammals. How PF's response to damage is largely unknown beyond a few major players. Checkpoint kinase 2 (CHEK2) primarily activates the pro-apoptotic TRP63 TA isoform (TAp63) in response to damage. In contrast, somatic cells predominantly use another CHEK2 target TRP53. Our lab showed Chek2-/- female mice receiving IR retained their PF reserve and produced healthy pups. TAp63-/- females receiving low dose IR maintained PFs while Trp53-/- mice lost their PF reserve. Suggesting that TRP53 is dispensable for apoptosis in oocytes. In treatments with higher IR dose or chemotherapies, TAp63-/- females lose PF reserve while Chek2-/- females retain PF reserve. We predicted higher doses of IR and chemotherapies cause more damage, which activates a TAp63-independent mechanism. Indeed, TAp63-/- Trp53-/- double mutant females exposed to higher dose IR retained PF reserve suggesting TRP53 triggers oocyte elimination when a certain threshold of damage is reached. Analysis of TRP53 protein expression after high dose IR identified a unique form of TRP53 in purified oocytes and the absence of the typical ~53kDa protein, detected in somatic cells. Based on these observations we hypothesize TRP53 activity in oocytes is regulated by an oocyte-specific mechanism which either activates TRP53 or restricts its action until a specific threshold of damage occurs. This proposal will utilize genetic approaches (chimeric reconstituted ovaries) and proteomic approaches (mass spectrometry) to determine TRP53 regulation in response to ovarian damage. The aims of this proposed research are to (1) determine whether TRP53-dependent PF loss is triggered intrinsically in the oocyte or is due to damage signals from somatic granulosa cells to the oocyte and 2) determine how TRP53 activity is regulated in oocytes by identifying unique post-translational modifications and/or protein interactions associated with TRP53-dependent PF loss. Defining oocyte-specific mechanisms regulating pro-apoptotic TRP53 activity in response to damage will improve our understanding of the PF response to genotoxic agents and provide targets for therapeutics to prevent oocyte loss, infertility, and POI in patients receiving genotoxic treatments.


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 = -$1,678 )
2025	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	000	2	1/23/2025	NON-COMPETING CONTINUATION	-$1,678
														Subtotal = -$1,678

Issue Date FY: 2023 ( Subtotal = $33,976 )
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	000	2	4/12/2023	NON-COMPETING CONTINUATION	$33,976
														Subtotal = $33,976

Issue Date FY: 2022 ( Subtotal = $32,986 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	001	1	2/21/2022	NEW	$0
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	000	1	2/21/2022	NEW	$32,270
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	003	1	6/3/2022	NEW	-$1
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	002	1	4/22/2022	NEW	$717
														Subtotal = $32,986

Grand Total All Awards = $65,284

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The Role and Regulation of TRP53 Activity in Oocytes and Granulosa Cells After Radiation-induced Damage

Award Number: F31HD108973

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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