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Estradiol Regulation of Hypothalamic Astrocyte Glycogen

Award Number: R01DK109382
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/19/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2022

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Estradiol Regulation of Hypothalamic Astrocyte Glycogen - Abstract: Glycogen is a critical reserve of oxidizable fuel for brain neuron use during states of heightened activity or glucoprivation. Iatrogenic hypoglycemia is a recurring complication of obligatory meticulous control of insulin-dependent diabetes mellitus and poses a serious risk of neural injury. There is thus keen interest to maximize protection against harmful effects of hypoglycemia by cerebral glycogen. Our studies show that estradiol and hindbrain catecholamine neurotransmitter signals converge to regulate ventromedial hypothalamus nucleus (VMH) glycogen metabolic enzyme protein expression. This project will address the hypothesis that astrocyte adenosine 5’-mono-phosphate-activated protein kinase (AMPK) regulates VMH glycogen metabolism, and that estradiol acts via classical receptor-mediated signaling to control effects of basal and hypoglycemia-enhanced hindbrain noradrenergic input on sensor activity. Estrogen augmentation of the glycogen fuel reserve is presumed to correlate with prolonged local nerve cell energetic stability during hypoglycemia. Proposed research is guided by three Specific Aims: 1) Determine effects of estradiol on hypothalamic metabolic sensory structure glycogen content in normo- and hypoglycemic ovariectomized female rats; 2) Assess the role of VMH astrocyte estrogen receptor variants in AMPK- mediated glycogen metabolic responses to glucoprivation; and 3) Determine substrates for interaction of hindbrain catecholamine and estrogen regulation of VMH astrocyte glycogen metabolism. This project will use a combinatory in situ immunocytochemistry/laser-capture microdissection/high-sensitivity qPCR and Western blot approach for quantitative cell type-specific molecular profiling; pharmacologic tools for manipulation of glycogen metabolic enzyme activity; nano- technological devices for selective knockdown of astrocyte protein expression; paired glycogen densitometric histochemistry and nerve cell AMPK/phosphoAMPK Western blot analyses to correlate high-resolution quantitative glycogen maps with VMH metabolic sensory nerve cell AMPK activity; and scanning particle-induced X-ray emission spectrometry to perform single-cell microanalysis of electrolyte correlates of VMH neuron electrical activity, and to quantify effects of estradiol on hypoglycemic patterns of transynaptic anterograde transport of Mn, a reliable indicator of neuron activation, between hindbrain A2 noradrenergic neurons and the VMH. This work will utilize an innovative assembly of investigative strategies to identify cellular and molecular mechanisms of estrogen regulation of astrocyte glycogen mass, knowledge that can be leveraged to advance development of therapeutic strategies for neuro- protective amplification of brain glycogen levels.


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: 2023 ( Subtotal = -$1,048 )
2023	2020	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVENUE	MONROE	LA	71209	OUACHITA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/7/2023	NON-COMPETING CONTINUATION	-$1,048
														Subtotal = -$1,048

Issue Date FY: 2020 ( Subtotal = $352,726 )
2020	2020	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVE	MONROE	LA	71209	OUACHITA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/14/2020	NON-COMPETING CONTINUATION	$352,726
2020	2019	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVE	MONROE	LA	71209	OUACHITA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	8/26/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $352,726

Issue Date FY: 2019 ( Subtotal = $352,726 )
2019	2019	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVE	MONROE	LA	71209	OUACHITA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/28/2019	NON-COMPETING CONTINUATION	$352,726
														Subtotal = $352,726

Issue Date FY: 2018 ( Subtotal = $352,726 )
2018	2018	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVE	MONROE	LA	71209	OUACHITA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/9/2018	NON-COMPETING CONTINUATION	$352,726
														Subtotal = $352,726

Issue Date FY: 2017 ( Subtotal = $352,726 )
2017	2017	UNIVERSITY OF LOUISIANA AT MONROE	700 UNIVERSITY AVE	MONROE	LA	71209	OUACHITA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/28/2017	NON-COMPETING CONTINUATION	$352,726
														Subtotal = $352,726

Issue Date FY: 2016 ( Subtotal = $336,736 )
2016	2016	UNIVERSITY OF LOUISIANA	700 UNIVERSITY AVENUE	MONROE	LA	71209	OUACHITA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/19/2016	NEW	$336,736
														Subtotal = $336,736

Grand Total All Awards = $1,746,592

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Estradiol Regulation of Hypothalamic Astrocyte Glycogen

Award Number: R01DK109382

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/19/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2022

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