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。

• 批准号: 8880264
• 负责人: TingTing Hong
• 金额: $ 24.9万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8880264
• 关键词: Adult; Age; American; Biochemical; Biological Markers; Biology; Biopsy; Biotinylation; Blood; Blood Circulation; Blood Tests; Calcium; Calcium Signaling; Cardiac; Cardiac Myocytes; Cardiac development; 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; Prognostic Marker; 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; prognostic value; skeletal; tool; trafficking; ventricular assist device

Project Summary 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.

项目概要 超过 500 万美国人患有心力衰竭 (HF)，每年新增病例超过 50 万例 在日益严重的流行病中。然而心力衰竭进展的病理生理学仍然知之甚少 因此，我们做出治疗决定的能力仍然有限。开发更具体和 需要与心力衰竭进展直接相关的预后生物标志物来改善临床管理。我有 最近发现一种关键的支架蛋白 BIN1 对于钙处理改变的发病机制很重要 在人类心力衰竭中。有了这些知识，我的长期目标是开发一种新型的心脏储备的心力衰竭生物标志物 通过了解正常和患病心肌细胞中 BIN1 的生物学和钙处理。这 这个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 衰竭的人类心肌细胞中 BIN1 表达降低，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 HF 钙瞬变调节的知识空白 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 目的是确定 BIN1 在 Cav1.2 运输和钙瞬时调节中对失败的人类的作用 心肌细胞。定量 rtPCR、蛋白质印迹、ELISA、免疫荧光和 T 管分级分离将 用于评估失败和非失败人类中 BIN1 和 Cav1.2 的细胞表达和定位 心肌细胞。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 表达作为终末期心力衰竭进展的诊断和预后测试 人类心肌病患者。定量免疫荧光将用于心脏活检以确定 心室 BIN1 表达水平，用于分析临床收缩参数和结果数据。具体的 目标 #3 是确定血清 BIN1 作为心肌病心脏储备的新型预后 HF 生物标志物 患者。将通过心脏特异性 ELISA 在大量心肌病人群中测量血清 BIN1 来自 UCSF 心力衰竭诊所的患者和年龄匹配的正常对照人群进行分析 临床数据。该贡献预计将确定 BIN1 作为 HF 介体和生物标志物，以帮助追踪 心力衰竭的进展并预测临床结果。这一贡献将是巨大的，因为 这一发现将改变当前监测疾病进展的心肌健康评估模式 并指导心力衰竭的治疗策略。本申请提出的研究具有创新性 因为它专注于 HF、组织和血清 BIN1 水平的新诊断和预后测试，可评估 心脏储备通过直接反映个体心肌细胞的生化健康状况。