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Understanding The Role Of FSHR Oligomerization And Trafficking In Transducing Age-dependent Changes In FSH Glycoforms

Award Number: R01HD113570
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: 08/19/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Understanding The Role Of FSHR Oligomerization And Trafficking In Transducing Age-dependent Changes In FSH Glycoforms - Project Summary/Abstract Although ovarian aging is a natural physiological process, cessation of ovarian function at midlife increases susceptibility to the development of co-morbidities, such as osteoporosis, which decrease quality of life and increases healthcare burden. There is currently no intervention for preventing/delaying this, highlighting an unmet need for novel approaches, e.g. extending ovarian lifespan, to tackle this. Key mediators of ovarian function are follicle stimulating hormone (FSH) and its receptor (FSHR). FSH is a glycoprotein hormone, with two predominant glycoforms identified; partially glycosylated FSH (FSH18/21) and fully glycosylated FSH (FSH24). FSH glycoforms have distinct functional properties, with FSH18/21 displaying faster binding kinetics and more potent and distinct signal pathway activation than FSH24. Interestingly, age-related changes in human pituitary extracts have been reported, with FSH18/21 predominant in women of reproductive prime and FSH24 predominant in peri-menopausal/menopausal women. The increase in less potent FSH24 coincides with increasing ovarian resistance to FSH reported during peri-menopause. Yet, how these functional differences in FSH modulate the actions of FSHR within the aging ovary remain unknown and will be explored by this project. Increasingly important ways that G protein-coupled receptors direct signal and functional diversity is via oligomerization (association of receptor protomers into dimers and oligomers), and endosomal trafficking. Our recent work suggests that FSH18/21 and FSH24 distinctly modulate FSHR oligomerization, correlating with differences in FSH glycoform-dependent cAMP production. Our preliminary data suggest that FSH glycoforms may route FSHR to different endosomal compartments, with cAMP production dependent on FSHR internalization. This project aims to determine how FSH glycoforms modulate FSHR oligomerization and trafficking in young and aging ovaries, and functional impact thereof. The working hypothesis is FSH glycoforms mediate distinct FSHR oligomerization signatures and FSHR trafficking within the young and aging ovary, with defined functional consequences. Using a novel N terminal tagged FLAG-FSHR knock in mouse, high resolution imaging and multiomics ATACseq and RNAseq approaches, Aim 1 will determine how FSHR oligomerization and signaling is modulated in granulosa cells during folliculogenesis and aging, and how disrupting FSHR oligomerization impacts FSH glycoform function. Aim 2 will determine how FSH glycoforms direct FSHR endosomal routing and role of these compartment in signal activation and downstream functions. Successful completion of these aims will elucidate how unique ovarian FSHR oligomerization and trafficking signatures direct signal pathway activation and transcriptomic and functional outputs by FSH glycoforms, during aging. This is the first step in the discovery pipeline to identifying novel strategies to improve ovarian function and health in aging women.


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 = $352,847 )
2025	2025	KING'S COLLEGE LONDON	STRAND	LONDON				GBR	Child Health and Human Development Extramural Research	000	2	7/21/2025	NON-COMPETING CONTINUATION	$352,847
														Subtotal = $352,847

Issue Date FY: 2024 ( Subtotal = $386,855 )
2024	2024	KING'S COLLEGE LONDON	STRAND	LONDON				GBR	Child Health and Human Development Extramural Research	000	1	8/19/2024	NEW	$386,855
														Subtotal = $386,855

Grand Total All Awards = $739,702

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Understanding The Role Of FSHR Oligomerization And Trafficking In Transducing Age-dependent Changes In FSH Glycoforms

Award Number: R01HD113570

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: 08/19/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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