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Identifying genes required for digestive physiology and lipid metabolism

Award Number: R01DK093399
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: 09/01/2013
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Identifying genes required for digestive physiology and lipid metabolism - Intestinal absorption of dietary nutrients is an important process contributing to the etiology of multiple metabolic diseases that represent ~30% of worldwide mortality. An organism’s response to a high-fat meal (HFM) requires coordination between multiple cell types in digestive tissues as well as the gut microbiota. Enterocytes (EC) are the absorptive cells of the intestine that coordinate this response by temporarily storing lipids in cytosolic lipid droplets (LD) and ultimately preparing them for circulation to distal tissues in ApoB- containing lipoproteins (BLP). In parallel, enteroendocrine cells (EEC) sense and communicate nutrient information to other cells and tissues via calcium-dependent hormone and neurotransmitter release. While the roles of these cells in postprandial physiology are broadly acknowledged, the specific mechanisms mediating EC and EEC postprandial responses to high-fat meal (HFM) and how microbiota influence those responses remain unresolved. Our research team pioneered the zebrafish system for studies of lipid metabolism and host-microbiota interaction. Over the past 10 years of this award, we have developed and applied highly innovative tools in the zebrafish system to reveal new mechanisms of lipid metabolism, EEC physiology, and host-microbiota interaction. The central hypothesis of this renewal is that a coordinated dynamic response to HFM between EC and EEC is mediated by a suite of microbe-influenced transcription factors that ultimately alter BLP and LD levels and turnover. Our research team has developed a set of novel tools to measure digestive organ lipid uptake, transport, storage, and signaling. These include the first family of in vivo reporter lines to quantify BLP size, numbers and turnover, as well as LD protein dynamics. In Aim 1, we will apply these new tools along with genetic analyses to define the dynamics underlying LD and BLP responses to HFM and microbes. We have previously used genetic approaches in zebrafish to identify host transcription factors mediating responses to HFM and microbiota, and recently performed the first single cell nuclei RNAseq analysis of an entire animal at a range of timepoints following a HFM. This approach allows us to interrogate the transcriptional networks driving the postprandial response of digestive organs at unprecedented levels of cellular and temporal granularity. In Aim 2, we will use these resources to define the transcriptional regulatory pathways mediating intestinal epithelial response to HFM. We have also established tools for measuring EEC responses to nutrients and microbes in zebrafish, and used them to reveal a novel microbiota-mediated EEC postprandial adaptation after a HFM. In Aim 3, we will define the mechanisms underlying this microbiota- induced EEC adaptation. This competitive renewal leverages long-standing partnerships between three field- leading labs with a powerful set of mutant and novel transgenic reporter lines to elucidate the relationships between EC, EEC, and microbiota. The zebrafish displays extensive homologies to that of humans and mice and provides technical advantages not available in mammals that enable the proposed studies.


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 = $606,592 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	2/28/2025	NON-COMPETING CONTINUATION	$606,592
														Subtotal = $606,592

Issue Date FY: 2024 ( Subtotal = $689,927 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	11	4/3/2024	COMPETING CONTINUATION	$333,483
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	3/18/2024	COMPETING CONTINUATION	$689,927
2024	2022	CARNEGIE INSTITUTION OF WASHINGTON	5241 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	3/8/2024	NON-COMPETING CONTINUATION	$0
2024	2022	CARNEGIE INSTITUTION OF WASHINGTON	5241 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	10	4/3/2024	NON-COMPETING CONTINUATION	-$333,483
														Subtotal = $689,927

Issue Date FY: 2022 ( Subtotal = $636,363 )
2022	2022	CARNEGIE INSTITUTION OF WASHINGTON	5251 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	7/8/2022	NON-COMPETING CONTINUATION	$636,363
														Subtotal = $636,363

Issue Date FY: 2021 ( Subtotal = $636,363 )
2021	2021	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/13/2021	NON-COMPETING CONTINUATION	$636,363
														Subtotal = $636,363

Issue Date FY: 2020 ( Subtotal = $636,363 )
2020	2020	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	7/24/2020	NON-COMPETING CONTINUATION	$636,363
														Subtotal = $636,363

Issue Date FY: 2019 ( Subtotal = $636,363 )
2019	2019	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	7/23/2019	NON-COMPETING CONTINUATION	$636,363
2019	2018	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	12/6/2018	COMPETING CONTINUATION	$50,072
2019	2017	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/6/2018	NON-COMPETING CONTINUATION	-$50,072
														Subtotal = $636,363

Issue Date FY: 2018 ( Subtotal = $645,707 )
2018	2018	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	9/17/2018	COMPETING CONTINUATION	$645,707
2018	2017	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	9/17/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $645,707

Issue Date FY: 2017 ( Subtotal = $416,034 )
2017	2017	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	8/25/2017	NON-COMPETING CONTINUATION	$416,034
2017	2016	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/1/2017	EXTENSION WITH OR WITHOUT FUNDS	$26,063
2017	2015	CARNEGIE INSTITUTION OF WASHINGTON	1530 P ST NW	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/1/2017	NON-COMPETING CONTINUATION	-$26,063
														Subtotal = $416,034

Issue Date FY: 2016 ( Subtotal = $501,614 )
2016	2016	CARNEGIE INSTITUTION OF WASHINGTON	1530 P. STREET N. W.	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	9/1/2016	EXTENSION WITH OR WITHOUT FUNDS	$501,614
														Subtotal = $501,614

Issue Date FY: 2015 ( Subtotal = $501,033 )
2015	2015	CARNEGIE INSTITUTION OF WASHINGTON	1530 P. STREET N. W.	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/13/2015	NON-COMPETING CONTINUATION	$501,033
														Subtotal = $501,033

Issue Date FY: 2014 ( Subtotal = $530,616 )
2014	2014	CARNEGIE INSTITUTION OF WASHINGTON	1530 P. STREET N. W.	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/8/2014	NON-COMPETING CONTINUATION	$530,616
														Subtotal = $530,616

Issue Date FY: 2013 ( Subtotal = $532,124 )
2013	2013	CARNEGIE INSTITUTION OF WASHINGTON	1530 P. STREET N. W.	WASHINGTON	DC	20005	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/3/2013	NEW	$532,124
														Subtotal = $532,124

Grand Total All Awards = $6,969,099

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Identifying genes required for digestive physiology and lipid metabolism

Award Number: R01DK093399

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: 09/01/2013

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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