Name: Summary of the probe development efforts to identify activators of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF). ..more
Table of Contents
Targets
| Sequence: troponin C, slow skeletal and cardiac muscles [Homo sapiens] Protein Family: EFh Gene:TNNC1 Related Protein 3D Structures |
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Depositor Specified Assays
| AID | Name | Type | Comment |
|---|---|---|---|
| 493008 | Fluorescence-based biochemical primary high throughput screening assay to identify activators of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF) | screening | Primary screen (RTF activators in singlicate) |
| 504382 | Counterscreen for activators of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF): Fluorescence-based biochemical assay to identify fluorescence artifacts | screening | Counterscreen (Fluorescence artifacts in triplicate) |
| 504383 | Fluorescence-based biochemical high throughput confirmation assay for activators of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF) | screening | Confirmation screen (Calcium sensitivity of cardiac RTF in triplicate) |
| 504697 | Counterscreen for activators of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF): Fluorescence-based biochemical high throughput dose response assay to identify fluorescence artifacts | confirmatory | Dose response counterscreen (Fluorescence artifacts in triplicate) |
| 504698 | Fluorescence-based biochemical high throughput dose response assay for activators of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF) | confirmatory | Dose response (Calcium sensitivity of cardiac RTF in triplicate) |
| 602231 | Assay provider mechanism-of-action assay for activators of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF): biochemical assay to identify activators of the Ca2+-sensitivity of cardiac muscle contraction/tension | other | Assay provider mechanism-of-action assay (Ca2+-sensitivity of cardiac muscle contraction/tension activators) |
| 602232 | Assay provider mechanism-of-action assay for activators of the calcium sensitivity of cardiac Regulated Thin Filaments (RTF): absorbance-based biochemical assay to identify sensitizers of the Ca2+ sensitivity of cardiac myofibrillar ATPase | other | Assay provider mechanism-of-action assay (Ca2+ sensitivity of cardiac myofibrillar ATPase sensitizers) |
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_ACT_SUMMARY
Name: Summary of the probe development efforts to identify activators 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 activators 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, sensitization, sensitizer, fluorescence, fluorophore, IANBD, FLINT, activate, activator, activation, 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.
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_ACT_SUMMARY
Name: Summary of the probe development efforts to identify activators 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 activators 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, sensitization, sensitizer, fluorescence, fluorophore, IANBD, FLINT, activate, activator, activation, 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.
Additional Information
Grant Number: 1 R21 NS064821-01
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