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Steroid Receptor Crosstalk and Pathogenesis of Uterine Fibroids

Award Number: R01HD100563
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: 08/02/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Steroid Receptor Crosstalk and Pathogenesis of Uterine Fibroids - Project Summary Uterine fibroids (leiomyomoas) are the most common gynecologic tumor in women of reproductive age. Although these tumors are considered benign, they cause significant gynecologic and reproductive dysfunction. The molecular mechanisms that regulate the development and growth of uterine fibroids are not well-understood, which has resulted in limited, non-invasive therapeutic options. As such, uterine fibroids are the leading indication for hysterectomy in the United States. There is a critical need for new therapeutic interventions that involve selectively targeting the pathways that promote fibroid growth. We have recently discovered that activation of the glucocorticoid receptor (GR) promotes uterine fibroid cell proliferation. Moreover, we found that glucocorticoids induce a unique transcriptional response in uterine fibroid cells compared to normal myometrium. Studies in tumors of the breast and endometrium demonstrates that steroid hormone crosstalk allows context- specific signaling supporting tumor growth and is associated with a poor prognosis. Our preliminary data in the uterus indicates that GR demonstrates crosstalk with the sex hormone receptors, estrogen (ER) and progesterone (PR) receptor, known factors that induce uterine fibroid growth. A mechanistic understanding of glucocorticoid action in the uterus is limited, and thus, glucocorticoid signaling represents a previously unexplored pathway contributing to the pathogenesis of uterine fibroids. We hypothesize that GR functions as a critical transcriptional regulatory factor contributing to the pathogenesis of uterine fibroids. We propose to test our hypotheses in three specific aims. In Specific Aim 1, we will define the mechanisms responsible for the differential responses to glucocorticoids in uterine fibroids compared to normal myometrial cells. In Specific Aim 2, we will define the molecular mechanism by which GR regulates uterine fibroid cell proliferation. Finally, the goal of Aim 3 will be to discover how steroid hormone crosstalk regulates gene expression in uterine fibroid cells. The proposed work is innovative because our studies represent the first investigation into the actions of GR and the interplay of steroid hormone receptors in uterine fibroid cells. By defining the processes by which glucocorticoid signaling promotes fibroid cell proliferation, these studies will generate new data to advance our understanding of this highly prevalent gynecological disease. Successful completion of these studies may open the door to the development of interventions that selectively target GR regulatory factors or down-stream signaling molecules of GR for the non-invasive treatment of uterine fibroids.


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 = $347,771 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	5	5/8/2024	NON-COMPETING CONTINUATION	$347,771
														Subtotal = $347,771

Issue Date FY: 2023 ( Subtotal = $351,284 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	4	6/2/2023	NON-COMPETING CONTINUATION	$351,284
														Subtotal = $351,284

Issue Date FY: 2022 ( Subtotal = $351,284 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	3	5/5/2022	NON-COMPETING CONTINUATION	$351,284
														Subtotal = $351,284

Issue Date FY: 2021 ( Subtotal = $409,901 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	003	2	5/4/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	2	4/29/2021	NON-COMPETING CONTINUATION	$353,767
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	1	1/14/2021	SUPPLEMENT FOR EXPANSION	$30,838
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	002	2	4/30/2021	SUPPLEMENT FOR EXPANSION	$25,296
														Subtotal = $409,901

Issue Date FY: 2020 ( Subtotal = $384,945 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	1	8/2/2020	NEW	$384,945
														Subtotal = $384,945

Grand Total All Awards = $1,845,185

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Steroid Receptor Crosstalk and Pathogenesis of Uterine Fibroids

Award Number: R01HD100563

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: 08/02/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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