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Characterization of Estrogen Sensitive Hypothalamic Glucose Sensing Neurons

Award Number: F31DK093331
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2011
PERIOD OF PERFORMANCE END DATE: 06/30/2015

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Characterization of Estrogen Sensitive Hypothalamic Glucose Sensing Neurons - DESCRIPTION (provided by applicant): Glucose sensing neurons (GSN) of the ventromedial hypothalamus (VMH) are believed to play a role in the regulation of energy and glucose homeostasis. However, the underlying mechanisms by which GSNs fulfill this role remain elusive. The current obesity epidemic and the rise in the prevalence of Type II Diabetes Mellitus (TIIDM) underscore the necessity to clarify these mechanisms and potentially illuminate novel therapeutic targets for these diseases. This is especially important for females since there is a greater incidence of obesity and TIIDM in females yet virtually all studies of GSNs have been performed in males. We have previously shown, in male mice, that VMH GSNs are dysfunctional during TIIDM. The strong correlation between estrogen receptor (ER) expression, in both sexes, and the location of VMH GSNs within the ventrolateral VMH suggests that estrogen regulates GSNs. This project hypothesizes that ER activation attenuates VMH GSN sensitivity to decreased glucose. Thus diminished estrogen levels following menopause may enhance responsiveness of GSNs to glucose decreases. This could lead to inappropriate signals of energy deficit and initiation of inappropriate compensatory mechanisms during energy sufficiency. Such a response may explain the increased susceptibility to TIIDM in post-menopausal females. To test this hypothesis, the pre-doctoral fellow will first determine whether glucose-excited or glucose-inhibited neurons are ER positive (either alpha or beta) using immunohistochemical and single-cell PCR methodologies. The neurotransmitter phenotype of these neurons will also be determined in order to better understand their role in energy homeostasis. Secondly, electrophysiological patch-clamp techniques will be used to determine how estrogen and the membrane impermeable BSA-conjugated estrogen regulate the acute activity as well as the glucose sensitivity of GSNs. The fellow will also utilize inhibitors of potential ER signaling molecules and western blot analysis to understand the mechanism of estrogenic regulation of VMH GSNs sensitivity. Using these same techniques, the fellow will investigate the effects of ER1 or ER2 ablation on the glucose sensitivity of VMH GSNs via the use of steroidogenic factor-1 driven ER1- or ER2-knockout mice (VMH exclusive knockout) and selective ER1 or ER2 antagonist application. Finally, using a fluorescent retrograde tracer, the fellow will determine whether estrogen-sensitive GSNs project directly to the anterior pituitary or to the preoptic area where they could potentially relay nutrient status information influencing the reproductive state of the individual.


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: 2017 ( Subtotal = -$2,761 )
2017	2012	UNIVERSITY OF MEDICINE AND DENTISTRY OF NJ (INC)							Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/18/2017	NON-COMPETING CONTINUATION	-$2,761
														Subtotal = -$2,761

Issue Date FY: 2014 ( Subtotal = $29,287 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/25/2014	NON-COMPETING CONTINUATION	$29,287
														Subtotal = $29,287

Issue Date FY: 2013 ( Subtotal = $28,843 )
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/6/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$28,843
														Subtotal = $28,843

Issue Date FY: 2012 ( Subtotal = $28,843 )
2012	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/14/2012	NON-COMPETING CONTINUATION	$28,843
														Subtotal = $28,843

Issue Date FY: 2011 ( Subtotal = $28,411 )
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/15/2011	NEW	$28,411
														Subtotal = $28,411

Grand Total All Awards = $112,623

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Characterization of Estrogen Sensitive Hypothalamic Glucose Sensing Neurons

Award Number: F31DK093331

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2011

PERIOD OF PERFORMANCE END DATE: 06/30/2015

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