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Role of the F-Bar Protein CIP4 in Cardiac Hypertrophy

F-Bar 蛋白 CIP4 在心脏肥大中的作用

基本信息

批准号：
9024232
负责人：
Michael Seth Kapiloff
金额：
$ 38.38万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9024232
关键词：
Adrenergic Agents Adult Amino Acids Amyloid beta-Protein Angiotensin II Angiotensin II Receptor Apoptosis Binding Binding Proteins Biosensor C-terminal Calcineurin Calmodulin Cardiac Cardiac Myocytes Catalytic Domain Catecholamines Cations Cessation of life Chronic Chronic stress Complex Cytoskeletal Proteins Cytoskeleton Dependovirus Development Diagnosis Disease Enzymes Family Fibrosis Fluorescence Resonance Energy Transfer G-Protein-Coupled Receptors Gene Expression Growth Guanosine Triphosphate Phosphohydrolases Heart Heart Hypertrophy Heart failure Hypertrophy In Vitro Infusion procedures Ion Channel Isoenzymes Knockout Mice Light Mediating Membrane Membrane Proteins Modeling Monomeric GTP-Binding Proteins Mus Muscle Cells Myocardial N-terminal Neonatal Neurosecretory Systems PPP3CA gene Pathologic Peptides Phenotype Phospholipids Phosphoric Monoester Hydrolases Play Prevention Process Proline-Rich Domain Protein Isoforms Protein Serine/Threonine Phosphatase Proteins Publications RHO Effector Domain Regimen Regulation Research Role Scaffolding Protein Signal Pathway Signal Transduction Signaling Molecule Site Specificity Structure Substrate Specificity Syndrome TRIP10 gene TRPC3 ion channel Testing Therapeutic Ventricular amphiphysin calcineurin phosphatase cardiogenesis cdc42 GTP-Binding Protein cell type constriction genetic regulatory protein in vivo interstitial member mortality new therapeutic target novel polyproline pressure prevent protein protein interaction public health relevance receptor response rho scaffold selective expression

项目摘要

DESCRIPTION (provided by applicant): The cardiac response to chronic stress involves the activation of a signal transduction network that induces myocyte hypertrophy and that in disease promotes myocardial apoptosis and interstitial fibrosis contributing to the development of heart failure. The phosphatase calcineurin (CaN) plays a central role in these processes. In cardiac myocytes there are two different isoforms of the CaN catalytic subunit, Aα and Aβ, and yet only Aβ is required for myocyte hypertrophy. Because CaN isoforms have similar substrate specificity and share common binding partners, it is unclear why there would be functional differences between the isoenzymes. We recently performed a screen for CaNAβ-specific binding partners. One protein that bound CaNA specifically is CIP4, a member of the F-BAR family of membrane-associated proteins. With the exception of our recent publication showing that CIP4 is required for the hypertrophy of cultured neonatal ventricular myocytes, F-BAR proteins have not been studied in the heart. In this application, we test the hypothesis that by serving as a CaNAβ scaffold, CIP4 contributes to the regulation of cardiac myocyte hypertrophy. We propose that CIP4 binding co-localizes CaNAβ with upstream receptors, ion channels and/or other signaling molecules that specifically confer CaNAβ function in pathologic cardiac remodeling. Specific Aim 1: The Requirement for CIP4 in Cardiac Remodeling In Vivo. In light of our in vitro findings, we propose to characterize the cardiac phenotype of a new conditional, cardiac-specific CIP4 knock-out mouse. The mice will be studied both when unstressed and when subject to chronic transverse aortic constriction, β-adrenergic, and angiotensin II receptor stimulation. We anticipate that the CIP4 knock-out mouse will have relatively normal cardiac function when unstressed and will be protected from the cardiac remodeling induced by pressure overload and neuroendocrine stimulation. Specific Aim 2: Mechanisms underlying CIP4-CaNA signaling in myocytes. Using novel FRET biosensors that will detect Ca2+ and CaN activity at CIP4 complexes, we propose to study the regulation of CIP4-bound CaNAβ in cultured adult and neonatal myocytes. We will study the co-localization of CIP4 and CaNAβ in the myocyte and test whether, as in other cell types, CIP4 localization may be regulated by growth factor and G-protein coupled receptor stimulation and by Rho family GTPases. In addition, we will determine whether gene expression regulated by the CaN effectors NFATc and MEF2 requires CIP4 expression in vivo. Specific Aim 3: Therapeutic Disruption of CaNAβ Anchoring In Vivo. The central hypothesis of this application is that the unique role of CaNAβ in pathological myocyte hypertrophy is due to CaNAβ anchoring by specific scaffolds. We propose to express selectively in the cardiac myocyte anchoring disrupter peptides for CaNAβ in order to test whether disruption of CaNAβ anchoring can prevent pathological remodeling in response to long-term pressure overload and catecholamine infusion.