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Translational control by nutrients

Award Number: R01DK060596
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: 03/15/2002
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Translational control by nutrients - The ability to adapt to environmental challenges is critical for cellular and organismal function. A frequent challenge is dehydration which increases osmotic pressure on the cells causing water loss and cell shrinkage. Cells respond by accumulating organic osmolytes to accommodate decreases in cell volume and ionic strength in a process called osmoadaptation. This cellular stress response is critical for survival of all organisms and tissues. Defects in osmoadaptation induce a pro-inflammatory program that decreases cell survival and has implications for multiple pathologies, including inflammatory bowel disease, diabetes, cancer and dry eye syndrome. Diabetes associated hyperglycemic hyperosmolar syndrome (HHS) is life threatening. It is therefore important to understand the molecular mechanisms of osmoadaptation. Our application focuses on the regulation of protein synthesis during osmoadaptation, a critical process that is poorly understood. The overall goal of this proposal is to develop a mechanistic, transcriptome-wide understanding of translation regulation during osmoadaptation that will lead to development of therapeutics of diseases that cause decreased tissue osmotolerance. We will examine the function of key regulators, including the amino transporter SNAT2 for establishing osmoadaptive mRNA translation programs using Human Corneal Epithelial Cells (HCEs). Corneal Epithelial cells are the cells in the eye that develop the pathology of dry eye syndrome in diabetes. To develop a mechanistic, transcriptome-wide understanding of translation regulation during osmoadaptation we characterize the translation landscape during osmoadaptation and define the regulatory RNA features that control the changes in mRNA translation (Aim 1). We then focus on the interplay between translation regulation, amino acid homeostasis and liquid-liquid phase separation (LLPS) of RNA binding proteins (RBPs) during osmoadaptation and delineate how mTOR and SNAT2 activities affect the translation landscape in response to hyperosmotic stress (Aim 2). Finally, we examine the function of RBPs that link LLPS and translation regulation, by determining RNA binding patterns and LLPS for specific RBPs during osmoadaptation (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 = $677,299 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	23	8/2/2025	NON-COMPETING CONTINUATION	$0
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	5/30/2025	NON-COMPETING CONTINUATION	$677,299
														Subtotal = $677,299

Issue Date FY: 2024 ( Subtotal = $650,207 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	5/8/2024	NON-COMPETING CONTINUATION	$650,207
														Subtotal = $650,207

Issue Date FY: 2023 ( Subtotal = $681,302 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	21	4/28/2023	NON-COMPETING CONTINUATION	$677,298
2023	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	20	4/7/2023	COMPETING CONTINUATION	$4,004
2023	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	1/18/2023	COMPETING CONTINUATION	$0
														Subtotal = $681,302

Issue Date FY: 2022 ( Subtotal = $677,298 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	7/8/2022	COMPETING CONTINUATION	$677,298
														Subtotal = $677,298

Issue Date FY: 2011 ( Subtotal = $603,924 )
2011	2011	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	7/8/2011	COMPETING CONTINUATION	$78,505
2011	2011	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	3/24/2011	COMPETING CONTINUATION	$525,419
														Subtotal = $603,924

Issue Date FY: 2010 ( Subtotal = $307,287 )
2010	2010	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	4/23/2010	NON-COMPETING CONTINUATION	$307,287
														Subtotal = $307,287

Issue Date FY: 2009 ( Subtotal = $310,391 )
2009	2009	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	4/15/2009	NON-COMPETING CONTINUATION	$310,391
														Subtotal = $310,391

Issue Date FY: 2008 ( Subtotal = $310,391 )
2008	2008	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Digestive Diseases and Nutrition Research	000	7	4/2/2008	NON-COMPETING CONTINUATION	$310,391
														Subtotal = $310,391

Issue Date FY: 2007 ( Subtotal = $316,725 )
2007	2007	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Digestive Diseases and Nutrition Research	000	6	4/16/2007	COMPETING CONTINUATION	$316,725
														Subtotal = $316,725

Issue Date FY: 2006 ( Subtotal = $295,541 )
2006	2006	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Digestive Diseases and Nutrition Research	000	5	1/16/2006	NON-COMPETING CONTINUATION	$295,541
														Subtotal = $295,541

Issue Date FY: 2005 ( Subtotal = $344,077 )
2005	2005	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Digestive Diseases and Nutrition Research	000	4	1/27/2005	NON-COMPETING CONTINUATION	$302,654
2005	2005	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Digestive Diseases and Nutrition Research	001	4	3/14/2005	SUPPLEMENT FOR EXPANSION	$41,423
														Subtotal = $344,077

Issue Date FY: 2004 ( Subtotal = $343,138 )
2004	2004	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Digestive Diseases and Nutrition Research	001	3	5/3/2004	SUPPLEMENT FOR EXPANSION	$40,484
2004	2004	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Digestive Diseases and Nutrition Research	000	3	3/11/2004	NON-COMPETING CONTINUATION	$302,654
														Subtotal = $343,138

Issue Date FY: 2003 ( Subtotal = $378,322 )
2003	2003	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Digestive Diseases and Nutrition Research	000	2		NON-COMPETING CONTINUATION	$302,654
2003	2003	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Digestive Diseases and Nutrition Research	001	2		SUPPLEMENT FOR EXPANSION	$18,917
2003	2003	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Digestive Diseases and Nutrition Research	001	1		SUPPLEMENT FOR EXPANSION	$56,751
														Subtotal = $378,322

Issue Date FY: 2002 ( Subtotal = $361,013 )
2002	2002	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Digestive Diseases and Nutrition Research	000	1	3/13/2002	NEW	$361,013
														Subtotal = $361,013

Grand Total All Awards = $6,256,915

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Translational control by nutrients

Award Number: R01DK060596

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: 03/15/2002

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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