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DECONSTRUCTING INFLAMMATION AND ALTERED MICROBIOTA IN METABOLIC SYNDROME

Award Number: R01DK099071
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: 08/01/2013
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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DECONSTRUCTING INFLAMMATION AND ALTERED MICROBIOTA IN METABOLIC SYNDROME - Abstract Humanity is facing an epidemic of interrelated obesity-associated disorders collectively referred to as metabolic syndrome (Met Syn). Central features of Met Syn include insulin-resistance, hyperlipidemia, hepatic steatosis and hypertension, all of which can progress to highly morbid and costly diseases such as diabetes, cardiovascular disease, and liver failure. Met Syn is associated with systemic chronic low-grade inflammation (LGI). LGI is not merely a marker of Met Syn but, rather, LGI interferes with a panoply of metabolic signaling pathways, including insulin and leptin signaling, such that chronic LGI promotes Met Syn. Thus, better understanding of the underlying causes of LGI is germane to managing the Met Syn epidemic. Proposed causes of LGI include the notion that obesity itself leads to lipid overload, resulting in endoplasmic reticulum stress that induces the pro-inflammatory gene expression that defines LGI. However, the grant this application seeks to renew has shown that LGI, and subsequently Met Syn, can also originate from poor management of gut microbiota, which is, in fact, required for many aspects of Met Syn. While our hypothesis that alterations in microbiota promote LGI/Met Syn originated from study of mice with a genetically engineered innate immune deficiency, namely lack of the flagellin receptor toll-like receptor 5 (TLR5) it has since proven applicable to understanding how diet, particularly industrialization of the food supply, might be altering the microbiota-host relationship in a manner that promotes LGI and, subsequently, Met Syn. Indeed, we’ve found that a central feature of Met Syn in both mice and humans, is infiltration of bacteria into the normally near-sterile inner mucus layer. Such microbiota encroachment can activate pro-inflammatory signaling in the intestine and/or result in translocation of bacteria, and their products, into liver and adipose tissue thus driving LGI in these organs. In contrast, obese humans lacking microbiota encroachment also lacked Met Syn . Moreover, in mice, ablation of microbiota via antibiotics, germfree status, or maintaining gnotobiotic mice with the pathobiont-free microbiome, results in a seemingly analogous state of “healthy obesity” in response to a western-style diet (WSD). Together, these results underscore our central hypothesis that microbiota encroachment is a pivotal event in driving LGI and, subsequently Met Syn. This hypothesis holds that preventing or reversing microbiota encroachment will ameliorate Met Syn. Hence, we will propose to identify encroaching bacteria (Aim 1) and define how they drive LGI and impact metabolism (Aim 2). Furthermore, we will develop means to train the immune system to reduce microbiota encroachment and ameliorate Met Syn (Aim 3).


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 = $0 )
2025	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	4/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $476,258 )
2024	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	5/15/2024	NON-COMPETING CONTINUATION	$29,765
2024	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	11/17/2023	NON-COMPETING CONTINUATION	$446,493
														Subtotal = $476,258

Issue Date FY: 2023 ( Subtotal = $496,103 )
2023	2023	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	12/5/2022	NON-COMPETING CONTINUATION	$446,493
2023	2023	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	1/24/2023	NON-COMPETING CONTINUATION	$49,610
														Subtotal = $496,103

Issue Date FY: 2022 ( Subtotal = $496,449 )
2022	2022	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	9	12/20/2021	NON-COMPETING CONTINUATION	$446,804
2022	2022	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	9	3/25/2022	NON-COMPETING CONTINUATION	$49,645
2022	2021	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	12/8/2021	COMPETING CONTINUATION	$303
2022	2019	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	12/8/2021	NON-COMPETING CONTINUATION	-$303
														Subtotal = $496,449

Issue Date FY: 2021 ( Subtotal = $508,940 )
2021	2021	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	007	8	1/4/2021	COMPETING CONTINUATION	$508,940
2021	2019	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	006	7	12/25/2020	NON-COMPETING CONTINUATION	$0
2021	2019	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	008	7	2/19/2021	NON-COMPETING CONTINUATION	$0
2021	2015	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	10/1/2020	NON-COMPETING CONTINUATION	-$177
2021	2015	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	10/1/2020	NON-COMPETING CONTINUATION	-$2,792
2021	2015	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	3	10/3/2020	NON-COMPETING CONTINUATION	$424
2021	2015	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	3	10/3/2020	NON-COMPETING CONTINUATION	$177
2021	2015	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	10/1/2020	NON-COMPETING CONTINUATION	-$424
2021	2015	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	10/3/2020	NON-COMPETING CONTINUATION	$2,792
														Subtotal = $508,940

Issue Date FY: 2019 ( Subtotal = $453,103 )
2019	2019	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	6/25/2019	NON-COMPETING CONTINUATION	$453,103
														Subtotal = $453,103

Issue Date FY: 2018 ( Subtotal = $492,910 )
2018	2018	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	7/10/2018	NON-COMPETING CONTINUATION	$492,910
														Subtotal = $492,910

Issue Date FY: 2017 ( Subtotal = $484,951 )
2017	2017	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	8/18/2017	SUPPLEMENT FOR EXPANSION	$39,809
2017	2017	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	6/21/2017	NON-COMPETING CONTINUATION	$445,142
2017	2015	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/29/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $484,951

Issue Date FY: 2016 ( Subtotal = $445,142 )
2016	2016	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	33 GILMER STREET SOUTHEAST	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	7/29/2016	COMPETING CONTINUATION	$445,142
2016	2015	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	33 GILMER STREET SOUTHEAST	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/26/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $445,142

Issue Date FY: 2015 ( Subtotal = $359,732 )
2015	2015	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	33 GILMER STREET SOUTHEAST	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/7/2015	NON-COMPETING CONTINUATION	$340,988
2015	2015	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	33 GILMER STREET SOUTHEAST	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/17/2014	SUPPLEMENT FOR EXPANSION	$18,744
														Subtotal = $359,732

Issue Date FY: 2014 ( Subtotal = $296,000 )
2014	2014	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	33 GILMER STREET SOUTHEAST	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/14/2014	NON-COMPETING CONTINUATION	$296,000
														Subtotal = $296,000

Issue Date FY: 2013 ( Subtotal = $296,000 )
2013	2013	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	33 GILMER STREET SOUTHEAST	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/29/2013	NEW	$296,000
														Subtotal = $296,000

Grand Total All Awards = $4,805,588

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DECONSTRUCTING INFLAMMATION AND ALTERED MICROBIOTA IN METABOLIC SYNDROME

Award Number: R01DK099071

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: 08/01/2013

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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