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Investigation of Human Antigen R (HuR) as a Novel Mediator of Cardiac Hypertrophy

人类抗原 R (HuR) 作为心脏肥大新型介质的研究

基本信息

批准号：
9902502
负责人：
Michael Tranter
金额：
$ 35.55万
依托单位：
UNIVERSITY OF CINCINNATI
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：
2016-07-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902502
关键词：
Ablation Address Adult Angiotensins Antigens Cardiac Cardiac Myocytes Catheterization Chronic Coupled Data Development Echocardiography G alpha q Protein G-Protein-Coupled Receptors Genes Genetic Goals Hearing Heart Heart Hypertrophy Heart failure Histology Human Hypertension Hypertrophy Investigation Laboratories Lead Left Ventricular Hypertrophy MAP Kinase Gene Mediating Mediator of activation protein Molecular Morphology Mus Muscle Cells Nature Neonatal Outcome Pathologic Pathology Phenotype Phenylephrine Pressure Transducers Prevention Proteins Quantitative Reverse Transcriptase PCR RNA-Binding Proteins Rattus Research Role Signal Pathway Signal Transduction Stimulus Stress Testing Therapeutic Time Transforming Growth Factor beta Ventricular Ventricular Remodeling Western Blotting Work clinically relevant clinically significant constriction heart function heart preservation improved in vivo knock-down mouse model novel overexpression p38 Mitogen Activated Protein Kinase pressure prevent programs public health relevance receptor response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The long-term goals of my research are to increase our understanding of the molecular mechanisms that promote the development and progression of pathological cardiac hypertrophy. In pursuit of this goal, my laboratory has new data suggesting the RNA binding protein Human antigen R (HuR) is a novel mediator of pathological cardiac hypertrophy. HuR is activated downstream of pro-hypertrophic signaling mediators such as phenylephrine and angiotensin, and although it is highly expressed in cardiac myocytes, very little is known concerning the functional role of HuR in the heart. New preliminary data from my lab shows that HuR is activated in hypertrophic myocytes, and cardiac-specific deletion of HuR prevents pathological hypertrophy in response to pressure overload. Thus, our central hypothesis is that activation of HuR in the cardiac myocytes promotes pathological cardiac hypertrophy, while ablation of HuR is protective. Aim 1 will determine the functional impact and downstream signaling of HuR in pathological cardiac hypertrophy. The working hypothesis for is that development of pathological hypertrophy and the cardiac remodeling associated with the transition from the compensated to de-compensated state will be reduced in cardiac-specific HuR deletion mice following transverse aortic constriction (TAC). We have developed an inducible cardiac-specific HuR deletion mouse that will allow us to examine the clinically relevant scenario of HuR deletion before and after the initial hypertrophic stimulus to determine whether blockade of HuR at a later time point can and delay or rescue pathological progression of hypertrophy to heart failure. Aim 2 will identify the upstream signaling pathways that lead to HuR activation in myocytes and determine the functional impact of HuR in Gq-mediated hypertrophy. The working hypothesis is that HuR is a novel downstream signaling mediator of Gq-coupled GPCR-induced pathological hypertrophy. Activation of Gq-protein is observed in nearly every form of pathological hypertrophy, but the specific mechanisms by which its activation results in cardiac pathology have yet to be fully elucidated. Thus, our results are poised to make a significant impact in how we understand pathological hypertrophy with HuR as a key signaling node downstream of Gq activation in the hypertrophic myocyte. Our proposed studies will determine the functional role of HuR in the development and progression of pathological hypertrophy and identify the downstream targets of HuR in hypertrophic myocytes (Aim 1). We will also determine the upstream mechanisms by which HuR is activated in the hypertrophic heart and identify HuR as a novel mediator of Gq-dependent pathological hypertrophy (Aim 2). This work is clinically significance in that we will determine whether direct inhibition of HuR has translational value as a therapeutic target for the prevention or treatment of pathological hypertrophy.