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Sphingolipids in Acute Kidney Injury and Disease Progression

Award Number: R01DK085259
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: 03/15/2010
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Sphingolipids in Acute Kidney Injury and Disease Progression - The overall goal of the current proposal is to understand the mechanisms by which targeting the sphingolipid pathway can prevent or attenuate progressive kidney fibrosis. ~20-40M people in the United States have kidney diseases and new treatments are urgently needed. Targeting the sphingolipid pathway serves as an important area for biological research that will undergird novel therapeutic interventions for the treatment of progressive kidney fibrosis. Sphingosine 1-phosphate (S1P) is the naturally occurring ligand of the S1P receptors (S1PR) and is present in both extracellular and intracellular compartments. The effects of extracellular S1P are mediated through S1PR1-5, which are differentially expressed by a variety of cell types. Intracellular S1P is controlled by manipulating S1P synthesis, degradation, or export. Intracellular S1P is a key signaling molecule that has multifunctional roles, depending on its compartmentalization. Intracellular S1P is generated by phosphorylation of sphingosine by two sphingosine kinases (Sphk1 and Sphk2). Sphk1 is localized to the cytoplasm and Sphk2 localized to the nucleus, mitochondria, and endoplasmic reticulum. We observed markedly attenuated renal fibrosis in Sphk2-/- mice compared to Sphk1-/- or WT mice and in mice with tissue specific deletion of Sphk2 in pericyte/perivascular cells. S1P generated by Sphk2 binds to and inhibits histone deacetylase (HDAC) activity and enhances gene expression. Recently Spns2 has been identified as an S1P export pathway; inhibition of S1P transport increases cytoplasmic S1P and inhibits production of fibrogenic factors in cultured kidney cells, and Spns2 deficient mice are associated with inflammatory disease conditions. Spns2 is highly expressed in proximal tubule, endothelium and pericytes. Lastly we found that a lead Spns2 inhibitor attenuated AKI. These findings lead us to hypothesize that compartmental control of S1P is a critical determinant of progressive kidney fibrosis. Aim 1 will test the hypothesis that nuclear Sphk2-deficiency protects mice from kidney fibrosis. We will determine whether the enzymatic activity or the nuclear localization of Sphk2 are necessary for fibrosis. Aim 2 will test the hypothesis that Spns2 inhibition or Spns2 deficiency protects mice from progressive kidney fibrosis. We will determine whether 1) global Spns2 deficient mice are protected from fibrosis and 2) mice treated with a lead Spns2 inhibitor, are protected from fibrosis. Aim 3. Will test the hypothesis that control of kidney parenchymal export of S1P is critical in attenuating fibrosis. We hypothesize that the protective effect is due to decreased export of S1P in proximal tubule cells, endothelial cells or pericytes. We will generate pericyte, endothelial and proximal tubule Spns2-/- mice and determine the effect on fibrosis. We will perform in vitro studies and determine the role of compartmental control of S1P pericytes, endothelial cells or proximal tubule cells factors that control pericyte to myofibroblast transition. We believe that these studies will lead to further understanding of the pathogenesis of progressive kidney fibrosis and provide the foundation for the development of novel therapeutics agents.


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: 2023 ( Subtotal = $489,079 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	3/29/2023	NON-COMPETING CONTINUATION	$489,079
														Subtotal = $489,079

Issue Date FY: 2022 ( Subtotal = $489,079 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	4/13/2022	NON-COMPETING CONTINUATION	$489,079
														Subtotal = $489,079

Issue Date FY: 2021 ( Subtotal = $489,079 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	10	3/11/2021	NON-COMPETING CONTINUATION	$489,079
2021	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	3/9/2021	COMPETING CONTINUATION	$669
2021	2018	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	3/9/2021	NON-COMPETING CONTINUATION	-$669
														Subtotal = $489,079

Issue Date FY: 2020 ( Subtotal = $490,020 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	2/13/2020	COMPETING CONTINUATION	$490,020
2020	2018	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	2/4/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $490,020

Issue Date FY: 2018 ( Subtotal = $426,935 )
2018	2018	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	6/28/2018	NON-COMPETING CONTINUATION	$426,935
														Subtotal = $426,935

Issue Date FY: 2017 ( Subtotal = $426,935 )
2017	2017	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	7/11/2017	NON-COMPETING CONTINUATION	$426,935
														Subtotal = $426,935

Issue Date FY: 2016 ( Subtotal = $426,935 )
2016	2016	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	7/6/2016	NON-COMPETING CONTINUATION	$426,935
														Subtotal = $426,935

Issue Date FY: 2015 ( Subtotal = $442,055 )
2015	2015	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/23/2015	COMPETING CONTINUATION	$442,055
														Subtotal = $442,055

Issue Date FY: 2013 ( Subtotal = $305,282 )
2013	2013	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/20/2013	NON-COMPETING CONTINUATION	$20,562
2013	2013	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/4/2013	NON-COMPETING CONTINUATION	$284,720
														Subtotal = $305,282

Issue Date FY: 2012 ( Subtotal = $316,355 )
2012	2012	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/6/2012	NON-COMPETING CONTINUATION	$316,355
														Subtotal = $316,355

Issue Date FY: 2011 ( Subtotal = $316,355 )
2011	2011	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/26/2011	NON-COMPETING CONTINUATION	$28,760
2011	2011	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/3/2011	NON-COMPETING CONTINUATION	$287,595
														Subtotal = $316,355

Issue Date FY: 2010 ( Subtotal = $385,000 )
2010	2010	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/15/2010	NEW	$385,000
														Subtotal = $385,000

Grand Total All Awards = $5,003,109

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Sphingolipids in Acute Kidney Injury and Disease Progression

Award Number: R01DK085259

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: 03/15/2010

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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