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BioAssay: AID 504337

Summary of the probe development efforts to identify inhibitors of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF)

Name: Summary of the probe development efforts to identify inhibitors of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF). ..more
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AID: 504337
Data Source: The Scripps Research Institute Molecular Screening Center (RTF_INH_SUMMARY)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2011-02-22
Modify Date: 2012-02-06
Targets
Depositor Specified Assays
AIDNameTypeComment
493244Fluorescence-based biochemical primary high throughput screening assay to identify inhibitors of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF)screeningPrimary screen (calcium sensitivity of cardiac RTF inhibitors in singlicate)
504635Fluorescence-based biochemical high throughput confirmation assay for inhibitors of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF)screeningConfirmation screen (calcium sensitivity of cardiac RTF inhibitors in triplicate)
504742Fluorescence-based biochemical high throughput dose response assay for inhibitors of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF)confirmatoryDose response (calcium sensitivity of cardiac RTF inhibitors in triplicate)
602245Assay provider mechanism-of-action assay for inhibitors of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF): biochemical assay to identify inhibitors of the Ca2+-sensitivity of cardiac muscle contraction/tensionotherAssay provider mechanism-of-action assay (inhibitors of the Ca2+-sensitivity of cardiac muscle contraction/tension)
602246Assay provider mechanism-of-action assay for inhibitors of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF): absorbance-based biochemical assay to identify desensitizers of the Ca2+ sensitivity of cardiac myofibrillar ATPaseotherAssay provider mechanism-of-action assay (desensitizers of the Ca2+ sensitivity of cardiac myofibrillar ATPase)
Description:
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: James D. Potter, University of Miami School of Medicine
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R21 NS064821-01
Grant Proposal PI: James D. Potter, University of Miami School of Medicine
External Assay ID: RTF_INH_SUMMARY

Name: Summary of the probe development efforts to identify inhibitors of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF).

Description:

Cardiomyopathies are myocardial diseases that often lead to cardiac remodeling to compensate for deficiencies in cardiac output (1). Cardiomyopathies are characterized as having systolic dysfunctions (i.e. reduced ejection fraction) in dilated cardiomyopathy or diastolic dysfunctions (i.e. impaired relaxation) in hypertrophic and restrictive cardiomyopathies (2). The regulated thin filament (RTF) is a multi-protein complex responsible for switching cardiac muscle contraction on and off in a calcium dependent manner. Mutations in the genes encoding RTF subunits are often the etiological agents for dilated, hypertrophic and restrictive cardiomyopathies. The RTF is comprised of troponin C (TnC), troponin I (TnI), troponin T (TnT), tropomyosin (Tm) and F-actin. Notably, a hallmark of RTF subunit gene mutations in cardiomyopathies is their ability to alter the calcium sensitivity of cardiac muscle contraction and the morphology of the heart (3). Since multiple forms of cardiomyopathies exist, the identification of new drugs that sensitize (+) or desensitize (-) the calcium sensitivity could potentially reverse these aberrant changes. Moreover, there are no calcium desensitizers in clinical use today. As a result of this HTS campaign, the identification of RTF calcium sensitivity modulators may serve as useful tools for elucidating the roles of these proteins in cardiac muscle contraction and disease (4).

Summary of Probe Development Effort:

This probe development effort is focused on the identification of inhibitors of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.

References:

1. Fatkin D, Graham RM. Physiol Rev. 2002 Oct;82(4):945-80. Molecular mechanisms of inherited cardiomyopathies.
2. Griffin, B. P., and Topol, E. J. (2004) Manual of Cardiovascular Medicine, 2nd Ed., pp. 101-142, Lippincott Williams and Wilkins, Philadelphia.
3. Dweck, D., Hus, N., and Potter, J. D. (2008) Challenging current paradigms related to cardiomyopathies. Are changes in the Ca2+ sensitivity of myofilaments containing cardiac troponin C mutations (G159D and L29Q) good predictors of the phenotypic outcomes? J Biol Chem 283, 33119-28.
4. Ingraham, R. H., and Swenson, C. A. (1984) Binary interactions of troponin subunits. J Biol Chem 259, 9544-8.

Keywords:

Summary, Summary AID, RTF, regulated thin filament, troponin C type I, TNC, TNNC, CMD1Z, CMH13, TNNC1, muscle, cardiac, contraction, contractile, calcium, desensitization, desensitizer, fluorescence, fluorophore, IANBD, FLINT, inhibit, inhibitor, inhibition, modulate, modulator, primary, primary screen, uHTS, HTS, high throughput screen, 1536, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Comment
This assay monitors the activity of recombinant RTF, which is a complex of 5 proteins. Protein and gene identifiers for one of the components (rabbit fast skeletal alpha actin), was not available in the NCBI database.
Additional Information
Grant Number: 1 R21 NS064821-01

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