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The Aging Pituitary/Gonadal Axis

Award Number: P01AG029531
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2009
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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The Aging Pituitary/Gonadal Axis - Project Summary/Abstract - Overall This integrated program project was pursuant to the discovery of naturally occurring, partially glycosylated follicle-stimulating hormone (FSH) glycoforms by the Bousfield laboratory. Two of these glycoforms possessed 3 of 4 N-glycans, exhibited greater biological activity, and were more abundant than fully-glycosylated FSH in young women. Furthermore, hypo-glycosylated FSH variants exhibited an age-dependent decrease concomitant with a well-known decline in fertility in women. Projects are organized to reflect the recognition of the importance of the development of numerous mouse genetic models in previous funding periods inspired by biochemical advances in understanding of the FSH glycoforms, and which now, will inspire in turn, such studies at the signaling, trafficking, and structural biology levels. In Project 1(Kumar), powerful genetic models now make it possible to study each specific glycoform independently, both by injection of purified glycoform preparations into Fshb-null mice as well as in transgenic mice expressing FSH18, FSH21, or FSH24. Advances in single-cell RNA-sequencing coupled with a transgenic line that expresses green fluorescent protein specifically in gonadotropes permit evaluation of the more than 50 enzymes responsible for N-linked oligosaccharide synthesis. Since non-ovarian targets of FSH have raised concerns and confusion for women undergoing IVF, several mouse models were devised to address questions raised by conflicting experimental outcomes, beginning with deletion of the Fshr gene, which would effectively eliminate all forms of putative FSHR proteins, including alternative splicing. In Project 2(Davis), studies involving FSH glycoform signals within primary cultures of granulosa cells, focus on the disparate responses of ovarian target cells to biased agonists FSH18, FSH21, and FSH24. Two major, differentially glycoform-regulated transcription factors (TF), CREB and YAP1, will have their downstream pathways characterized in granulosa cells. Granulosa cells of young and advanced age mice and women will provide basic information relevant to translational efforts. The interface between FSH and FSHR, both monomeric and oligomeric receptor forms, will be studied in Project 3(Jonas). Activation of cAMP accumulation is now known to involve FSHR dynamics that will be evaluated, including internalization. FSH glycoforms are anticipated to alter FSHR conformation to varying degrees, leading to biased agonist signals. Project 4(Bousfield) will incorporate FSHR into lipid nanodiscs to provide a means to evaluate glycoform-FSHR- membrane interactions, using cryogenic electron microscopy (cyro-EM). This has been done with LH and TSH receptors (LHR & TSHR) and those studies have revealed the ligand binding site undergoes a major rotation, lifting it away from the membrane, during receptor activation. The location of FSH oligosaccha-rides is on the back side of the hormone, away from the hormone-receptor interface, which suggests interaction with the cell membrane or membrane proteins. Taken together, the projects integrate FSH glycoform signaling at overlapping levels ranging from the intact organism to the glycosylated hormone itself.


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 = $2,137,513 )
2024	2024	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT ST # 38	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	002	12	6/21/2024	NON-COMPETING CONTINUATION	$2,137,513
2024	2023	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT ST # 38	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	001	11	3/19/2024	COMPETING CONTINUATION	$96,940
2024	2022	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT ST # 38	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	10	3/19/2024	SUPPLEMENT FOR EXPANSION	-$96,940
														Subtotal = $2,137,513

Issue Date FY: 2023 ( Subtotal = $2,263,722 )
2023	2023	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT ST	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	11	5/25/2023	COMPETING CONTINUATION	$2,263,722
														Subtotal = $2,263,722

Issue Date FY: 2022 ( Subtotal = $298,576 )
2022	2022	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT ST	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	10	6/17/2022	SUPPLEMENT FOR EXPANSION	$344,492
2022	2022	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT ST	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	001	10	8/26/2022	SUPPLEMENT FOR EXPANSION	-$45,916
														Subtotal = $298,576

Issue Date FY: 2021 ( Subtotal = $1,717,046 )
2021	2021	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT ST	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	10	7/14/2021	NON-COMPETING CONTINUATION	$1,717,046
														Subtotal = $1,717,046

Issue Date FY: 2020 ( Subtotal = $1,709,158 )
2020	2020	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT ST	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	9	8/7/2020	NON-COMPETING CONTINUATION	$1,709,158
														Subtotal = $1,709,158

Issue Date FY: 2019 ( Subtotal = $1,709,158 )
2019	2019	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT ST	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	8	8/12/2019	NON-COMPETING CONTINUATION	$1,709,158
														Subtotal = $1,709,158

Issue Date FY: 2018 ( Subtotal = $1,691,954 )
2018	2018	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT ST	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	7	8/3/2018	NON-COMPETING CONTINUATION	$1,691,954
														Subtotal = $1,691,954

Issue Date FY: 2017 ( Subtotal = $1,801,381 )
2017	2017	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT ST	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	6	9/1/2017	COMPETING CONTINUATION	$1,801,381
														Subtotal = $1,801,381

Issue Date FY: 2014 ( Subtotal = $55,517 )
2014	2013	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT STREET	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	5	12/31/2013	NON-COMPETING CONTINUATION	$55,517
														Subtotal = $55,517

Issue Date FY: 2013 ( Subtotal = $1,165,852 )
2013	2013	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT STREET	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	5	5/2/2013	NON-COMPETING CONTINUATION	$1,110,335
2013	2013	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT STREET	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	001	5	12/31/2013	NON-COMPETING CONTINUATION	$55,517
														Subtotal = $1,165,852

Issue Date FY: 2012 ( Subtotal = $1,233,584 )
2012	2012	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT STREET	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	4	3/27/2012	NON-COMPETING CONTINUATION	$1,233,584
														Subtotal = $1,233,584

Issue Date FY: 2011 ( Subtotal = $1,232,843 )
2011	2011	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT STREET	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	3	3/21/2011	NON-COMPETING CONTINUATION	$1,154,390
2011	2011	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT STREET	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	001	3	6/9/2011	NON-COMPETING CONTINUATION	$78,453
														Subtotal = $1,232,843

Issue Date FY: 2010 ( Subtotal = $1,259,142 )
2010	2010	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT STREET	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	001	2	4/13/2010	NON-COMPETING CONTINUATION	-$1,259,142
2010	2010	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT STREET	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	2	4/2/2010	NON-COMPETING CONTINUATION	$1,259,142
2010	2010	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT STREET	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	002	2	4/20/2010	NON-COMPETING CONTINUATION	$1,259,142
														Subtotal = $1,259,142

Issue Date FY: 2009 ( Subtotal = $1,344,624 )
2009	2009	WICHITA STATE UNIVERSITY	1845 FAIRMOUNT STREET	WICHITA	KS	67260	SEDGWICK	USA	Aging Research	000	1	4/7/2009	NEW	$1,344,624
														Subtotal = $1,344,624

Grand Total All Awards = $19,620,070

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The Aging Pituitary/Gonadal Axis

Award Number: P01AG029531

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2009

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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