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Astrocyte insulin resistance-induced neuroendocrine defects in pubertal delay and hypogonadotropic hypogonadism

Award Number: R01HD104418
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Astrocyte insulin resistance-induced neuroendocrine defects in pubertal delay and hypogonadotropic hypogonadism - Astrocytes are known to provide support to gonadotropin releasing hormone (GnRH) neurons that control the reproductive axis, for example by releasing prostaglandin E2 (PGE2) required for fertility. Astrocytes may also play a critical role in the brain as metabolic sensors. In response to insulin, astrocytes increase glucose uptake across the blood brain barrier and release metabolites and gliotransmitters to support neuronal function. We have recently demonstrated a unique biological role for astrocytes in coupling fertility to energy availability. We found that the absence of insulin signaling in astrocytes delays puberty, causes hypogonadotropic hypogonadism, and dramatically reduces fertility. This finding is particularly exciting since numerous studies have shown neuronal insulin sensing is unnecessary for reproduction. We have also found that loss of astrocyte insulin sensing reduces PGE2 synthase levels, leading us to hypothesize that astrocyte insulin sensing facilitates GnRH release by promoting astrocyte PGE2 release. New preliminary data suggest that insulin signaling via FOXO pathways alter the transcription of enzymes in the PGE2 biosynthesis pathway, such as COX-2. We will test our hypothesis by pursuing three specific aims. Aim 1) Define the relevant temporal & spatial parameters of astrocyte insulin signaling. Using the tet-on genetic targeting system, we will test whether astrocytes must sense insulin during adulthood or prior to puberty in order to permit normal reproductive function. Astrocyte-specific viral cre administration will also determine the importance of astrocyte insulin sensing in the arcuate nucleus and the rostral preoptic area. Aim 2) Determine the impact of insulin signaling on astrocyte PGE2 gliotransmitter production proximal to reproductive circuits. Measurement of regional PGE2 production will be complemented by AAV targeted disruption of Cox-2 production by astrocytes to determine its importance for fertility. Finally, we will determine whether Kiss1 neurons sense PGE2, leading to altered GnRH release. Aim 3) Determine the molecular role of the insulin/ FOXO pathway in astrocyte PGE2 synthesis. An astrocyte cell line will be used to systematically investigate the major aspects of insulin/FOXO/COX signaling, including phosphorylation, localization, promoter occupancy, and quantitative transcriptional activity measurements. Finally, we will ablate insulin signaling pathways in astrocytes to determine their effect on fertility and PGE2 production. Collectively, these studies will identify how insulin signaling in astrocytes sustains reproductive circuit function. This work will elucidate what may be the dominant mechanism in the mammalian brain whereby insulin permits normal fertility and pubertal maturation. Our results will advance our long-term goal of finding treatment targets for impaired fertility in patients recovering from energy deficits, obese and diabetic populations, and others with idiopathic hypogonadotropic hypogonadism.


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 = $536,227 )
2025	2025	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Child Health and Human Development Extramural Research	001	4	4/24/2025	NON-COMPETING CONTINUATION	$53,623
2025	2025	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Child Health and Human Development Extramural Research	000	4	1/21/2025	NON-COMPETING CONTINUATION	$482,604
														Subtotal = $536,227

Issue Date FY: 2024 ( Subtotal = $527,805 )
2024	2024	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Child Health and Human Development Extramural Research	001	3	5/2/2024	NON-COMPETING CONTINUATION	$47,982
2024	2024	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Child Health and Human Development Extramural Research	000	3	1/18/2024	NON-COMPETING CONTINUATION	$479,823
														Subtotal = $527,805

Issue Date FY: 2023 ( Subtotal = $551,677 )
2023	2023	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Child Health and Human Development Extramural Research	000	2	5/5/2023	NON-COMPETING CONTINUATION	$551,677
														Subtotal = $551,677

Issue Date FY: 2022 ( Subtotal = $533,137 )
2022	2022	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Child Health and Human Development Extramural Research	000	1	4/22/2022	NEW	$533,137
														Subtotal = $533,137

Grand Total All Awards = $2,148,846

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Astrocyte insulin resistance-induced neuroendocrine defects in pubertal delay and hypogonadotropic hypogonadism

Award Number: R01HD104418

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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