BIN1 is a mediator and marker of cardiac reserve in heart failure.

BIN1 是心力衰竭心脏储备的调节因子和标志物。

基本信息

批准号：
8300530
负责人：
TingTing Hong
金额：
$ 9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300530
关键词：
Adult Age American Biochemical Biological Markers Biology Biopsy Biotinylation Blood Blood Circulation Blood Tests Calcium Calcium Signaling Cardiac Cardiac Myocytes Cardiomyopathies Cells Cellular biology Clinic Clinical Clinical Data Clinical Management Data Decision Making Development Diagnosis Diagnostic Diagnostic tests Disease Progression Enzyme-Linked Immunosorbent Assay Epidemic Extracellular Matrix Proteins Face Failure Fractionation Functional disorder Future Goals Health Heart Heart Transplantation Heart failure Human Image Immunofluorescence Immunologic Individual Inflammatory Knowledge L-Type Calcium Channels Left Life Link Measures Mediator of activation protein Medical Membrane Mission Modeling Monitor Morbidity - disease rate Mus Muscle Myocardial Myocardial Contraction Myocardial tissue Myocardium Outcome Pathogenesis Patients Perinatal Population Population Analysis Protein Isoforms Proteins Public Health Recovery Regulation Research Role Scaffolding Protein Serum Specificity Staging Surface Testing Therapeutic Tissues United States Ventricular Western Blotting Work amphiphysin 2 base cytokine improved innovation insight mortality novel novel diagnostics outcome forecast prognostic skeletal tool trafficking ventricular assist device

项目摘要

DESCRIPTION (provided by applicant): Over five million Americans have heart failure (HF), with more than 500,000 new cases added each year in what is a growing epidemic. Yet the pathophysiology of heart failure progression remains poorly understood and, as a result, our ability to make therapeutic decisions remains limited. Development of more specific and prognostic biomarkers that are directly tied to HF progression is required to improve clinical management. I have recently found that a key scaffolding protein, BIN1, is important to the pathogenesis of altered calcium handling in human HF. With this knowledge, my long term goal is to develop a novel HF biomarker of cardiac reserve through understanding the biology of BIN1 and calcium handling in normal and diseased cardiomyocytes. The objective of this particular application is to understand the role of BIN1 in regulation of the calcium transients in heart failure, and to use BIN1 to develop a diagnostic and prognostic test in HF patients. My central hypothesis is that BIN1 expression is reduced in failing human cardiomyocytes, and that BIN1 levels in tissue and serum correlate with recovery potential of myocardial tissue. The rationale is that successful completion of the proposed research will fill a gap in the knowledge of BIN1 based regulation of calcium transients in HF which helps to develop an innovative diagnostic and prognostic test of cardiac reserve in HF patients. Specific Aim #1 is to identify the role of BIN1 in Cav1.2 trafficking and calcium transient regulation in failing human cardiomyocytes. Quantitative rtPCR, western blot, ELISA, immunofluorescence, and T-tubule fractionation will be used to assess the cellular expression and localization of BIN1 and Cav1.2 in failing and non-failing human cardiomyocytes. In adult mouse cardiomyocyte models, surface biotinylation and live-cell calcium imaging will be used to study Cav1.2 trafficking and calcium transients in BIN1 depleted cardiomyocytes. Specific Aim #2 is to identify myocardial tissue BIN1 expression as a diagnostic and prognostic test of HF progression in end-stage human cardiomyopathy patients. Quantitative immunofluorescence will be used on heart biopsies to determine ventricular BIN1 expression level for analysis with clinical contractile parameters and outcome data. Specific Aim #3 is to identify serum BIN1 as a novel prognostic HF biomarker of cardiac reserve in cardiomyopathy patients. Serum BIN1 will be measured by cardiac specific ELISA in a large population of cardiomyopathy patients from the UCSF heart failure clinic and an age-matched normal control population for analysis with clinical data. The contribution is expected to identify BIN1 as a HF mediator and biomarker to help track the progression of heart failure and prognosticate clinical outcomes. This contribution will be significant because such discovery will shift current paradigm in myocardial health assessment for monitoring disease progression and guiding therapeutic strategies in heart failure. The research proposed in this application is innovative because it focuses on a new diagnostic and prognostic test of HF, tissue and serum BIN1 level, which assess cardiac reserve through directly reflecting the biochemical health of individual cardiomyocytes.

描述（由申请人提供）：超过 500 万美国人患有心力衰竭 (HF)，这种流行病日益严重，每年新增病例超过 500,000 例。然而，对心力衰竭进展的病理生理学仍然知之甚少，因此，我们做出治疗决策的能力仍然有限。为了改善临床管理，需要开发与心力衰竭进展直接相关的更具特异性和预后性的生物标志物。我最近发现一种关键的支架蛋白 BIN1 对于人类心力衰竭钙处理改变的发病机制很重要。有了这些知识，我的长期目标是通过了解 BIN1 的生物学以及正常和患病心肌细胞中的钙处理来开发一种新型心脏储备的 HF 生物标志物。这一特定应用的目的是了解 BIN1 在调节钙瞬变中的作用心力衰竭，并使用 BIN1 开发心力衰竭患者的诊断和预后测试。我的中心假设是 BIN1 表达在衰竭的人类心肌细胞中减少，并且组织和血清中的 BIN1 水平与心肌组织的恢复潜力相关。理由是，成功完成拟议的研究将填补基于 BIN1 的心力衰竭钙瞬变调节的知识空白，这有助于开发心力衰竭患者心脏储备的创新诊断和预后测试。具体目标#1 是确定 BIN1 在 Cav1.2 运输和衰竭人类心肌细胞钙瞬时调节中的作用。定量 rtPCR、蛋白质印迹、ELISA、免疫荧光和 T 管分级分离将用于评估 BIN1 和 Cav1.2 在衰竭和非衰竭人类心肌细胞中的细胞表达和定位。在成年小鼠心肌细胞模型中，表面生物素化和活细胞钙成像将用于研究 BIN1 耗尽的心肌细胞中的 Cav1.2 运输和钙瞬变。具体目标#2 是确定心肌组织 BIN1 表达，作为终末期人类心肌病患者心力衰竭进展的诊断和预后测试。定量免疫荧光将用于心脏活检以确定心室 BIN1 表达水平，以便分析临床收缩参数和结果数据。具体目标#3 是确定血清 BIN1 作为心肌病患者心脏储备的新型预后 HF 生物标志物。将通过心脏特异性 ELISA 对来自 UCSF 心力衰竭诊所的大量心肌病患者和年龄匹配的正常对照人群进行血清 BIN1 测量，以进行临床数据分析。该贡献预计将确定 BIN1 作为心力衰竭介质和生物标志物，以帮助跟踪心力衰竭的进展并预测临床结果。这一贡献将是意义重大的，因为这样的发现将改变当前心肌健康评估的范式，以监测疾病进展并指导心力衰竭的治疗策略。该申请提出的研究具有创新性，因为它专注于心力衰竭、组织和血清BIN1水平的新诊断和预后测试，通过直接反映个体心肌细胞的生化健康状况来评估心脏储备。