RedudionjofLDL-cholesterol through the: use;q^ mprtality and n(i6rb)<3ity caused by GO ro disease (GHD), Nevertheless, GHD remains the leading caijse of: death fbrnnen and vfi?3men in the United Stat^, OneireasQfi for the persistence of CHD may be the tacfebf:therapies'that;)riqrease;:(HE)L-chQieste^ ?lt'is:wiBll'established:that.,l-iDL-d'conGertti?!tion is-a'^ stripng,ihdeipendentjnver^ely^^^m^ Because of data Indicating that a 1 mg/dl increase in HDL.-C decreases CHD risk;by ^^^^ therapiesiihdt'yyili'.ieffe'diWjy.iele^ <3ri6 class''ibif'Comfiounds::that;'may have.great;"""""""" therapeutic potential are PHARd agonists, which in non'human primates can elevate HDLrG by 43-79% and apo/V-1, themajor apolipoprotein of HiDL, by 43i%. Irt this applicatiprv, j prpposetpdeflne;the mechanisms by which PPARftagtjhlstsiriGiuceHpL-G elevation in non-liymari primates, twill deteriTiine whether PPARS agonists increase HDL-G by: 1) altering HDL production or catabolism;2) changing the activity of plasma ITpasiis, lipid transfer proteins, and LGAT;3) mpdolating themRNA and protein expression of genes involved in HDL metabolism. In addition, I pnoppse to determine whether PPAR6 agonists elevate HDL-C in monkeys that have Ibeen treated with antisense oligonudeptides that suppress hepatic expression of ATP binding cass|0e,trarispdrter A;^ .iCAS'C^ deN^loprhisfit of rnbre-potent PPAR6 agbnlsts or other therapiesthateffeetiveiy increase HbL-C. which in turn could prevent CHD in hundreds of thousands pf people each year in the Onlted Statisss and around the world. Scientific data indicates that inGreasing HDL choiasterol may decree cause of death for men arid women in the United States. We propose to determine the mechanisms by which a new class of drugs, known as RPAR;delta agonists, increase HDL-Ghdlesterolin monkeys. Because of the high cjegr^ of similality between the bodies of studies yillproyideinsighlsf6i'the development of therapieis that could increase HDL and prevent the deaths of iiuhdreds of thousands of;people each year from heart disease.

Public Health Relevance

Scientific data indicates that increasing HDL cholesterol may decrease the risk of heart disease, the leading cause of death for men and women in the United States. We propose to determine the mechanisms by which a new class of drugs, known as PPAR delta agonists, increase HDL-cholesterol in monkeys. Because of the high degree of similarity between the bodies of humans and monkeys, we feel confidant that these studies will provide insights for the development of therapies that could increase HDL and prevent the deaths of hundreds of thousands of people each year from heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL088528-04
Application #
7769906
Study Section
Special Emphasis Panel (NSS)
Program Officer
Liu, Lijuan
Project Start
2009-02-15
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$247,703
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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