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Intercellular mechanisms of microglia activation in diet-induced obesity

Award Number: R01DK120321
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: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2022

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Intercellular mechanisms of microglia activation in diet-induced obesity - This is an administrative supplement request (PA-18-591) in response to NOT-AG-20-034 (Alzheimer's -focused Administrative supplements for NIH grants that are not focused on Alzheimer's disease) to our ongoing NIH grant 1R01DK120321-03 entitled “Intracellular mechanisms of microglia activation in diet-induced obesity”. This project aims to unmask the role of uncoupling protein 2 (UCP2)-mediated mitochondrial dynamics in microglia activation in the central regulation of energy homeostasis in order to develop better strategies for the treatment of metabolic disorders, such as obesity and type 2 diabetes. There are no Alzheimer’s Disease-related studies proposed in this grant. In response to NOT-AG-20-034, we request funds to test the hypothesis that UCP2-dependent microglia activation and neuroinflammation may impact the onset of the development of Alzheimer’s disease (AD) in genetic mouse model of AD by affecting histological and behavioral changes. Our preliminary studies show that inhibiting UCP2-dependent microglia activation in mice exposed to HFD feeding prevents neuroinflammation (microgliosis), protects from the development of metabolic disorders, such as obesity and type 2 diabetes, and also prevents changes in behaviors and hippocampal structure that are associated with aging and AD. As aging and obesity are risk factors for the development of neurodegenerative disorders such as Alzheimer’s disease (AD), we hypothesize that HFD-induced UCP2-dependent microglia activation plays a role in the onset of the development of AD and inhibition of this mechanism, by reducing chronic neuroinflammation, prevents and/or delays the onset of cortical and hippocampal histological and behavioral changes in AD. Thus, in this supplement we propose to assess the effect of selective and inducible deletion of UCP2 in microglial cells on the histology and behavior of AD mice [5xFAD mice (B6.Cg- Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax; Oakley H et al., 2006)] exposed to either standard chow diet or HFD, at different time points. Several littermate mice will be used as controls. Both male and female mice will be studied. Behavioral and histological studies will be performed at different time points to assess the role of microglia in the onset of AD development in this AD mouse model. The execution of these studies will deliver novel insights into the role of microglia and metabolism in AD.


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 = -$3 )
2024	2021	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	1/25/2024	SUPPLEMENT FOR EXPANSION	-$1
2024	2021	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/25/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$3

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	11/4/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $978,097 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	5	6/30/2021	NON-COMPETING CONTINUATION	$588,755
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	4/20/2021	SUPPLEMENT FOR EXPANSION	$405,000
2021	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/2/2021	NON-COMPETING CONTINUATION	-$476,976
2021	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	006	4	8/8/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$474,925
2021	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	3	8/8/2021	NON-COMPETING CONTINUATION	-$131,768
2021	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	4/5/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$461,318
2021	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	2	8/8/2021	SUPPLEMENT FOR EXPANSION	-$343,157
														Subtotal = $978,097

Issue Date FY: 2020 ( Subtotal = $608,744 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/14/2020	NON-COMPETING CONTINUATION	$608,744
														Subtotal = $608,744

Issue Date FY: 2019 ( Subtotal = $1,027,492 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/12/2019	NON-COMPETING CONTINUATION	$608,744
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/13/2019	SUPPLEMENT FOR EXPANSION	$418,748
														Subtotal = $1,027,492

Issue Date FY: 2018 ( Subtotal = $608,744 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/18/2018	NEW	$608,744
														Subtotal = $608,744

Grand Total All Awards = $3,223,074

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Intercellular mechanisms of microglia activation in diet-induced obesity

Award Number: R01DK120321

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: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2022

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