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Liver X Receptor in Diabetic Nephropathy and Cardiomyopathy

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Data Summary

Applicant	Levi, Moshe
E-Mail Address	moshe.levi@georgetown.edu
Project Title	Liver X Receptor in Diabetic Nephropathy and Cardiomyopathy
CBU ID	15GHSU2550
External SubContract ID	25034-69
Diabetic Complication	Nephropathy
Funding Program Group	Pilot & Feasibility [PF2015]
Abstract	Despite major advances in the treatment of diabetes, many patients continue to experience diabetes-related pathologies in major organ systems. Diabetic renal and cardiovascular disease remains leading causes of premature mortality in patients with diabetes. In addition, women with diabetes have 40% greater risk for death from all causes, and two times the risk for fatal and nonfatal vascular events, than men with the disease. Therefore, new strategies that target novel pathophysiological causes of microvascular and macrovascular disease in both men and women are urgently needed. We propose to generate pilot data to determine if targeting the Liver X Receptor (LXR) holds therapeutic promise for prevention and treatment of renal and cardiac disease in diabetic male and female mice. Our hypothesis is that in diabetes there is down regulation of LXR expression and activity in the kidney which results in increased cholesterol accumulation, activation of the inflammatory response, and endoplasmic reticulum stress, cellular processes that playa critical role in the pathogenesis of diabetic renal disease. Renal disease by itself induces or accelerates cardiovascular disease. We suggest that downregulation of LXR expression and activity in the cardiac tissue also further mediates cardiac disease. In Specific Aim 1 we will treat male and female a) nondiabetic control db-m mice and b) diabetic db-db mice with an LXR agonist. At the end of a 12 week treatment period with the LXR agonist DMHCA (1-3) we will determine effects of LXR agonist on: 1) renal function including glomerular filtration rate, albuminuria, and renal histopathology, 2) cardiac function including in vivo echo, cardiac histopathology, and markers of fibrosis and hypertrophy; 3) perform high resolution and label-free imaging for lipid accumulation, inflammation, oxidative stress, and fibrosis with CARS-TPE-SHG-FLIM microscopy. We will perform detailed biochemical studies to determine effects of the LXR agonist on i) cholesterol and lipid composition, ii) inflammation, and iii) endoplasmic reticulum stress. In Specific Aim 2 we will perform mechanistic studies in a) human podocytes and b) human cardiac myocytes to determine the effects of 1) LXRa or 2) LXR脽 overexpression. In cells grown with i) control media, ii) high glucose media, iii) media with fatty acids, and iv) media with high glucose and fatty acids, we will determine effects of LXRa or LXR脽 overexpression on a) cholesterol and lipid composition, b) inflammation, and c) endoplasmic reticulum stress. We will further check the ability of LXRa or LXR脽 overexpression in resisting i) cholesterol induced inflammation and ER stress in cells loaded with acetylated LDL in the presence of ACAT inhibitor, ii) thapsigargin induced ER stress, and iii) LPS induced inflammation.
Application PDF	Application Research Plan
Status	Contract Executed
Key Personnel
Salary Total Costs	31559
Supply Total Costs	12000
Equipment Total Costs	0
Travel/Other Total Costs	20441
Direct Costs	64000
Indirect Costs Proposed	35520
Total Costs Proposed	99520
Total Costs Approved	99520
Start Date	10/1/2015
End Date	9/30/2016
IFO Name	Gannon, Amy
IFO E-Mail Address	xenia@ucdenver.edu
IACUC/IRB No.	A3269-01
IACUC/IRB Institution	University of Colorado
Entity ID No.
Report Request Date	10/30/2016
T1D	NO

Type	Count
Invoices	4
Progress Reports	1

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Url	CBU ID	External ID	Institution	Date	Direct	Indirect	Invoice	Balance	PDF
View	15GHSU2550	25034-69	University of Colorado	8/8/2016	$17,889.27	$9,928.55	$27,817.82	$5.36	View PDF
View	15GHSU2550	25034-69	University of Colorado	4/15/2016	$42,270.16	$23,460.01	$65,730.17	$5.36	View PDF
View	15GHSU2550	25034-69	University of Colorado	10/21/2016	$1,221.56	$677.99	$1,899.55	$5.36	View PDF
View	15GHSU2550	25034-69	University of Colorado	10/10/2017	$2,615.49	$1,451.61	$4,067.10	$5.36	View PDF

Author	Complete Date	Report
Levi, Moshe	6/11/2017	View Progress Report Document

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