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EVALUATION OF PPARGAM-SPARING TZDS FOR TREATING NON-ALCOHOLIC FATTY LIVER DISEASE

Award Number: R42AA021228
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2009
PERIOD OF PERFORMANCE END DATE: 08/31/2013

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EVALUATION OF PPARGAM-SPARING TZDS FOR TREATING NON-ALCOHOLIC FATTY LIVER DISEASE - DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the United States. This condition encompasses both hepatic steatosis and the more severe non-alcoholic steatohepatitis. It is now estimated that 14-24% of the general population and up to 80% of morbidly obese subjects have contracted NAFLD. Untreated disease may progress to cirrhosis and lead to hepatic cancer. Cirrhosis now accounts for 12.5% of diabetes related deaths. In spite of the recognized need and degree of interest in the literature, there are no currently approved therapeutic agents for treatment of NAFLD and this unmet medical need will likely continue to increase in concert with the epidemic of obesity. The overall objective of the proposed research is to discover a PPAR?-sparing thiazolidinedione (TZD) which displays efficacy in a rodent model of non-alcoholic fatty liver disease (NAFLD) and demonstrates the necessary drug-like qualities to become a potential clinical candidate for human therapeutics. The TZD class of insulin sensitizing agents are conventionally thought to operate through binding to PPAR? receptors. However, it is the strong contention of the authors of this proposal that the undesirable effects of the TZDs are mediated by binding to PPAR? receptors. Moreover, it has recently been suggested that rosiglitazone, the prototypical PPAR? activator, could exert untoward acute cardiovascular effects. Contrary to the prevailing scientific view, the authors of this proposal believe that non-PPAR mediated mechanisms are responsible for the insulin sensitizing pharmacology. The co-founders of the Metabolic Solutions Development Company (MSDC) have conceived of TZDs which should display minimal or no binding to the PPAR? receptor and has extensively evaluated their activity in cellular models (brown adipose precursor cell differentiation) and in rodent models of Type 2 diabetes. In Phase I studies, we evaluated a PPAR-sparing analog on a rodent model of NAFLD and the results clearly show that it improves insulin sensitivity accompanied by increased ability of the liver to oxidize and clear fat. Thus, the positive completion of this project provides an excellent foundation for selecting and developing a PPAR?- sparing TZD for treatment of NAFLD devoid of the side effects typically associated with this class of medications. The experimental work planned for Phase II would build on and extend this technology to achieve the selection and initial preclinical development of an analog for treatment of NAFLD as well as the potential identification of a biomarker which could be useful for detection of early disease and to monitor therapeutic progress in clinical trials.


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: 2012 ( Subtotal = $610,998 )
2012	2012	METABOLIC SOLUTIONS DEVELOPMENT COMPANY	3133 ORCHARD VISTA DRIVE SE	GRAND RAPIDS	MI	49546	KENT	USA	Alcohol Research Programs	001	3	9/11/2012	SUPPLEMENT FOR EXPANSION	$50,000
2012	2012	METABOLIC SOLUTIONS DEVELOPMENT COMPANY	3133 ORCHARD VISTA DRIVE SE	GRAND RAPIDS	MI	49546	KENT	USA	Alcohol Research Programs	000	3	8/16/2012	NON-COMPETING CONTINUATION	$560,998
														Subtotal = $610,998

Issue Date FY: 2011 ( Subtotal = $563,804 )
2011	2011	METABOLIC SOLUTIONS DEVELOPMENT COMPANY	3133 ORCHARD VISTA DRIVE SE	GRAND RAPIDS	MI	49546	KENT	USA	Alcohol Research Programs	000	2	9/15/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$563,804
														Subtotal = $563,804

Grand Total All Awards = $1,174,802

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EVALUATION OF PPARGAM-SPARING TZDS FOR TREATING NON-ALCOHOLIC FATTY LIVER DISEASE

Award Number: R42AA021228

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/10/2009

PERIOD OF PERFORMANCE END DATE: 08/31/2013

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