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Small GTP Binding Proteins in Gastrointestinal Mucosa

Award Number: R01DK048370
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: 08/01/1997
PERIOD OF PERFORMANCE END DATE: 07/31/2027

Group Awards By:

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Small GTP Binding Proteins in Gastrointestinal Mucosa - For the past three decades, we have sought to elucidate mechanisms of vesicle trafficking mediated by Rab small GTPase that regulate apical membrane trafficking of key intestinal epithelial transporters that regulate polarized enterocyte function. These investigations led to the recognition of MYO5B and MYO5A as regulators of trafficking through its interaction with multiple Rab proteins. The interaction with Rab10 is based on the presence of a minor MYO5B splice variant coding for the 30 amino acid Exon D. Our determination that MHV M glycoprotein also interacted with MYO5B Exon D, led us to investigate a possible role for MYO5B+D in regulating M protein trafficking. We have successfully completed our major aims to characterize the regulation of M protein trafficking by MYO5B and Rab10, but we have not been able to demonstrate any obligate requirement for this interaction for MHV assembly or egress. We therefore feel that it is necessary to refocus our efforts on our main interests in regulation of gastrointestinal epithelial cells. Our overall goal in Year 5 of the grant is to establish new approaches to modifying Rab11a and Rab8a dependent trafficking pathways that are responsible for discrete aspects of apical enterocyte trafficking. We will therefore pursue two new initiatives this year: First, we will seek to identify specific small molecule inhibitors of the interaction of Rab11a and Rab8a with MYO5B. We will utilize the yeast 2-hybrid assay screening system developed in the first 4 years of the grant to perform high throughput screens of drug libraries. Candidate hits will be tested for the concentration dependence of their action against Rab11a interaction with MYO5B and high potency inhibitors will then be tested for their ability both to inhibit the interaction of endogenous Rab8a or Rab11a with GFP-MYO5B tail. Second, we will seek to identify Rab11a and Rab8a-specific trafficking pathways for apical transporters and enzymes in intestinal epithelial cells. We have created two novel mouse alleles, LSL-Green Lantern-MYO5B tail(YE/QR) and LSL-Scarlet-MYO5B tail(QL/YC) using internal departmental funds. We hypothesize that blockade of Rab11a dependent versus Rab8a dependent trafficking will lead to specific deficits in trafficking and alterations in epithelial physiology. To that end, we will cross each transgenic allele onto the Villin-CreERT2 driver allele for induction of expression in the intestine. We will also assess the sequestration of Rab8a and Rab11a as well as apically directed transporters (including NHE3, SGLT1 and CFTR) with the dominant negative trafficking inhibitors. These studies will allow us for the first time to assess the importance of Rab11a versus Rab8a dependent recycling pathways on the physiology of intestinal enterocytes in vivo.


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: 2026 ( Subtotal = $0 )
2026	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	30	5/17/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $615,274 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	30	9/8/2025	NON-COMPETING CONTINUATION	$615,274
														Subtotal = $615,274

Issue Date FY: 2024 ( Subtotal = $590,663 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	29	7/18/2024	NON-COMPETING CONTINUATION	$590,663
														Subtotal = $590,663

Issue Date FY: 2023 ( Subtotal = $615,259 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	28	7/24/2023	NON-COMPETING CONTINUATION	$615,274
2023	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	11/21/2022	NON-COMPETING CONTINUATION	-$15
														Subtotal = $615,259

Issue Date FY: 2022 ( Subtotal = $615,274 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	27	7/22/2022	NON-COMPETING CONTINUATION	$615,274
2022	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	26	11/29/2021	COMPETING CONTINUATION	$50,737
2022	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	11/29/2021	NON-COMPETING CONTINUATION	-$50,737
														Subtotal = $615,274

Issue Date FY: 2021 ( Subtotal = $633,524 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	26	7/13/2021	COMPETING CONTINUATION	$633,524
														Subtotal = $633,524

Issue Date FY: 2020 ( Subtotal = $384,899 )
2020	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	7/23/2020	NON-COMPETING CONTINUATION	$384,899
														Subtotal = $384,899

Issue Date FY: 2019 ( Subtotal = $384,900 )
2019	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	7/17/2019	NON-COMPETING CONTINUATION	$384,900
														Subtotal = $384,900

Issue Date FY: 2018 ( Subtotal = $373,652 )
2018	2018	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	23	9/14/2018	COMPETING CONTINUATION	$384,900
2018	2016	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	8/16/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$11,248
														Subtotal = $373,652

Issue Date FY: 2016 ( Subtotal = $343,650 )
2016	2016	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	6/29/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$343,650
2016	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	21	6/29/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $343,650

Issue Date FY: 2015 ( Subtotal = $341,475 )
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	5/7/2015	NON-COMPETING CONTINUATION	$341,475
														Subtotal = $341,475

Issue Date FY: 2014 ( Subtotal = $341,294 )
2014	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	6/13/2014	NON-COMPETING CONTINUATION	$341,294
														Subtotal = $341,294

Issue Date FY: 2013 ( Subtotal = $339,300 )
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	8/9/2013	COMPETING CONTINUATION	$339,300
														Subtotal = $339,300

Issue Date FY: 2011 ( Subtotal = $317,022 )
2011	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	6/27/2011	NON-COMPETING CONTINUATION	$317,022
														Subtotal = $317,022

Issue Date FY: 2010 ( Subtotal = $320,224 )
2010	2010	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	5/10/2010	NON-COMPETING CONTINUATION	$320,224
														Subtotal = $320,224

Issue Date FY: 2009 ( Subtotal = $323,459 )
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	4/29/2009	NON-COMPETING CONTINUATION	$323,459
														Subtotal = $323,459

Issue Date FY: 2008 ( Subtotal = $323,459 )
2008	2008	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Digestive Diseases and Nutrition Research	000	15	6/2/2008	COMPETING CONTINUATION	$323,459
														Subtotal = $323,459

Issue Date FY: 2007 ( Subtotal = $332,437 )
2007	2007	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Digestive Diseases and Nutrition Research	000	14	7/24/2007	NON-COMPETING CONTINUATION	$332,437
														Subtotal = $332,437

Issue Date FY: 2006 ( Subtotal = $342,365 )
2006	2006	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Digestive Diseases and Nutrition Research	000	13	8/1/2006	NON-COMPETING CONTINUATION	$342,365
														Subtotal = $342,365

Issue Date FY: 2005 ( Subtotal = $487,638 )
2005	2005	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Digestive Diseases and Nutrition Research	000	12	8/12/2005	NON-COMPETING CONTINUATION	$411,167
2005	2005	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Digestive Diseases and Nutrition Research	001	12	9/13/2005	SUPPLEMENT FOR EXPANSION	$76,471
														Subtotal = $487,638

Issue Date FY: 2004 ( Subtotal = $442,705 )
2004	2004	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Digestive Diseases and Nutrition Research	002	10	4/29/2004	SUPPLEMENT FOR EXPANSION	$31,538
2004	2004	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Digestive Diseases and Nutrition Research	001	11	8/23/2004	SUPPLEMENT FOR EXPANSION	$60,563
2004	2004	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Digestive Diseases and Nutrition Research	000	11	7/19/2004	NON-COMPETING CONTINUATION	$350,604
														Subtotal = $442,705

Grand Total All Awards = $10,460,315

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Small GTP Binding Proteins in Gastrointestinal Mucosa

Award Number: R01DK048370

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: 08/01/1997

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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