Version 2.1.1.0

Abstract

Grant Number:	1R43HL074479-01
PI Name:	BUSH, ERIK W.
PI Email:	erik.bush@myogen.com
PI Title:
Project Title:	MCIP1-Augmenting Drugs as New Heart Failure Therapeutics

Abstract: DESCRIPTION (provided by applicant): Heart failure, the common endpoint of many cardiovascular diseases, affects 700,000 individuals yearly in the United States with an annual cost of $10-40 billion. The expanding number of those afflicted with chronic heart failure and its persistently poor prognosis make it clear that additional novel treatment approaches are necessary. Progressive maladaptive cardiac hypertrophy is a key mechanism that significantly contributes to the deterioration of the failing human heart. The calcium-dependent phosphatase calcineurin (CN) plays a central role in hypertrophic signaling, being both necessary and sufficient for cardiac hypertrophy in vivo. Myocyte-enriched Calcineurin-lnteracting Protein-1 (MCIP1), a newly described CN inhibitory protein preferentially expressed in striated muscle, has recently been demonstrated to inhibit cardiac hypertrophy in response to genetic, pathologic and pharmacologic stimuli. We therefore hypothesize that small molecules which increase expression of endogenous MCIP1 protein may attenuate cardiac hypertrophy via tissue-selective inhibition of CN. Myogen has developed a high-throughput whole-cell immunoassay capable of reporting endogenous MCIP1 protein expression in primary cardiomyocytes. This Phase I proposal seeks to assess the feasibility of whether this high-throughput assay can identify lead compounds that increase MCIP1 protein expression and inhibit cardiomyocyte hypertrophy in vitro. If Phase I efforts are successful, Phase II will involve expanded screening, lead compound optimization and in vivo studies to assess the ability of lead compounds to attenuate and possibly reverse cardiac hypertrophy and subsequent failure.

Thesaurus Terms:
calcineurin, cardiovascular agent, drug design /synthesis /production, drug screening /evaluation, heart failure, immunologic assay /test, method development, ventricular hypertrophy
cardiac myocyte, chemical registry /resource, high throughput technology, protein quantitation /detection
laboratory rat, western blotting

Institution:	MYOGEN, INC.
	7575 W 103RD AVE, #212
	WESTMINSTER, CO 800214014
Fiscal Year:	2003
Department:
Project Start:	15-SEP-2003
Project End:	31-MAR-2004
ICD:	NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
IRG:	ZRG1

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