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Control of ovarian vascular remodeling by CCAAT/enhancer binding proteins alpha and beta

Award Number: R01HD109392
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/16/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Control of ovarian vascular remodeling by CCAAT/enhancer binding proteins alpha and beta - PROJECT SUMMARY/ABSTRACT Infertility occurs in approximately 15% of women of reproductive age in the United States. Approximately half of the cases involve impaired ovulation, the cause of which is often elusive. The aim of this project is to achieve new understanding of ovulatory defects that will serve as a foundation for effective treatment of infertility. It is known that obesity negatively impacts female fertility and ovulation, but the underlying mechanism remains to be elucidated. Recent findings highlight the crucial role of preovulatory ovarian vascular remodeling in successful ovulation: the ovulatory luteinizing hormone (LH) surge induces a series of vascular remodeling processes in the ovary, including changes in vascular permeability, vessel contraction and formation of new blood vessels. CCAAT/enhancer binding proteins alpha and beta (C/EBPα and C/EBPβ, jointly abbreviated C/EBPα/β) are rapidly induced in granulosa cells by the LH surge and function as important regulators of ovulation. Based on our preliminary data, which show the profound effects of C/EBPα/β deficiency on ovarian vascular remodeling in mice, we hypothesize that C/EBPα and C/EBPβ are key mediators by which the LH surge controls vascular remodeling in preovulatory ovaries. Given obesity’s negative impact on vascular function in general and on ovarian blood flow in women in particular, we also propose the novel concept that ovarian vascular remodeling is a key mediator between obesity and ovulation failure. This proposal first seeks to use murine models of ovulation failure and disrupted ovarian vascular remodeling to identify their regulatory mechanisms downstream of the LH surge, then addresses the knowledge deficit around obesity’s impact on ovarian vasculature. To achieve these goals we will apply 3-dimensional quantitative intravital imaging to a transgenic mouse line with ovary-specific ablation of C/EBPα/β to first define the specific vascular remodeling events regulated by C/EBPα/β in preovulatory ovaries, then determine in a diet-induced obese mouse model the impact of obesity on the activity of C/EBPα/β and vascular remodeling during ovulation. We will further seek understanding of cell type-specific mechanisms regulating preovulatory vascular remodeling and ovulation using single-cell, next-generation sequencing technologies; these approaches will also reveal whether epigenetic mechanisms regulating chromatin accessibility play a key role in preovulatory vascular remodeling and ovulation, and whether C/EBPα/β mediate this interaction. Successful completion of the proposed studies will advance our understanding of ovulation regulation and have a major impact by elucidating links among obesity, epigenetic regulation, and ovarian function, thus enabling improved treatment of many cases of female infertility.


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 = $338,335 )
2026	2026	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	5	5/22/2026	NON-COMPETING CONTINUATION	$338,335
														Subtotal = $338,335

Issue Date FY: 2025 ( Subtotal = $338,335 )
2025	2025	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	4	7/11/2025	NON-COMPETING CONTINUATION	$338,335
														Subtotal = $338,335

Issue Date FY: 2024 ( Subtotal = $335,897 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	3	5/6/2024	NON-COMPETING CONTINUATION	$335,897
														Subtotal = $335,897

Issue Date FY: 2023 ( Subtotal = $344,386 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	2	5/1/2023	NON-COMPETING CONTINUATION	$344,386
														Subtotal = $344,386

Issue Date FY: 2022 ( Subtotal = $346,448 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Child Health and Human Development Extramural Research	000	1	8/16/2022	NEW	$346,448
														Subtotal = $346,448

Grand Total All Awards = $1,703,401

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Control of ovarian vascular remodeling by CCAAT/enhancer binding proteins alpha and beta

Award Number: R01HD109392

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/16/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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