C-terminal Peptide of Cardiac Troponin I for the Treatment of Diastolic Hear Failure

心肌肌钙蛋白 I C 端肽治疗舒张性心力衰竭

• 批准号: 10850280
• 负责人: Jian-Ping Jin
• 金额: $ 28.12万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10850280
• 关键词: Aorta; ApoE knockout mouse; Attenuated; C-terminal; Cardiac; Cells; Clinical Data; Collaborations; Cytoskeleton; Development; Disease; Effectiveness; Environment; Etiology; Failure; Hearing; Heart failure; Human; Investigation; Laboratories; Learning; Lesion; Mechanics; Medical; Methodology; Molecular; Molecular Target; Myofibroblast; Parents; Pathogenesis; Pathologic; Peptides; Play; Prevention; Productivity; Protein Isoforms; Proteins; Reporting; Research; Research Personnel; Research Project Grants; Role; Surgical Valves; System; Therapeutic Effect; Tissues; Translations; Troponin; Troponin I; Ventricular Remodeling; aortic valve; aortic valve disorder; calcification; calponin; cell type; hemodynamics; innovation; insight; interstitial cell; knockout gene; molecular targeted therapies; mouse model; novel; osteogenic; prevent; programs; targeted treatment; tool; transdifferentiation; valve replacement

SUMMARY OF SUPPLEMENT RESEARCH Calcific aortic valve disease (CAVD) is a common and severe valvular disease that causes heart failure. Surgical valve replacement is currently the only available treatment. However, recent clinical data indicate that the pathological myocardial remodeling and failing continue after valve replacement, severely limiting the therapeutic effect on long-term survival. We have reported that knockout of the gene encoding calponin isoform 2 attenuates hyperchloremia-caused aortic valve calcification in ApoE knockout mice, suggesting a novel molecular target for the treatment and prevention of CAVD. Here we propose to expand the parent research project with new investigations into the role of calponin 2 in the pathogenesis and progression of CAVD and the underlying mechanisms for the development of non-surgical treatment and prevention. To further investigate the therapeutic effect of calponin 2 deletion or reduction on attenuating the pathogenesis and progression of CAVD and to understand the underlying molecular mechanism, we shall apply integrative multi-level approaches to pursue two supplement specific aims. Aim S1 is to characterize the longitudinal benefit of calponin 2 deletion and reduction for mitigating CAVD and the effectiveness in representative mouse models of different etiologies. The studies will investigate the states of disease in which calponin 2 reduction will effectively prevent attenuate or reverse the calcific lesion of aortic valve. Aim S2 is to understand the mechanoregulation of calponin 2 in calcific differentiation of aortic valvular interstitial cells. Aortic valve functions in a dynamic mechanical environment. Cellular mechanoregulation plays an important role in the pathogenesis of aortic valve calcification. Calponin 2 is a troponin-like cytoskeleton mechanoregulatory protein that is increased in calcified human aortic valves. Among the multiple cell types involved the pathogenesis of CAVD, we shall focus on the role of mechanoregulated functions of calponin 2 in aortic valve interstitial cells during trans-differentiation into myofibroblasts and osteogenic cells. The studies will learn mechanistic insights into the development of calponin 2-targeted treatment and prevention of CAVD in the context of valvular hemodynamics and pathological tissue remodeling. This supplement research is proposed on the basis of strong scientific premise and prior research, innovative molecular targets, testable hypothesis and multi-level integrative experimental systems. The anticipated results will have major scientific and medical implications. With demonstrated expertise in calponin research and in collaboration with CAVD expert, our productive team of investigators has all necessary technical capacities, methodology and tools, and mouse models to launch the new studies and make timely progresses to develop a more comprehensive research program toward translation into new non-surgical treatment and prevention of CAVD.

实验研究综述 钙化性主动脉瓣疾病（CAVD）是一种常见且严重的瓣膜疾病，可导致心力衰竭。 外科瓣膜置换术是目前唯一可用的治疗方法。然而，最近的临床数据表明， 瓣膜置换术后病理性心肌重构和衰竭仍在继续，严重限制了 对长期生存的治疗效果。我们已经报道了敲除编码钙调蛋白亚型的基因， 2减弱ApoE基因敲除小鼠中高血压引起的主动脉瓣钙化，提示了一种新的 治疗和预防CAVD的分子靶点。在这里，我们建议扩大父母的研究 该项目对钙调蛋白2在CAVD发病机制和进展中的作用进行了新的研究， 发展非手术治疗和预防的潜在机制。 为了进一步研究钙调蛋白2缺失或减少对减轻心肌梗死的治疗作用， CAVD的发病机制和进展，并了解潜在的分子机制，我们将应用 采取多层次的综合办法，以实现两个相辅相成的具体目标。目的S1是表征 钙调蛋白2缺失和减少对缓解CAVD的纵向益处以及 不同病因的代表性小鼠模型。这些研究将调查疾病的状态， 降低calponin 2可有效防止或逆转主动脉瓣钙化病变。目标S2是 了解钙调蛋白2在主动脉瓣间质细胞钙化分化中的机械调节作用。主动脉 阀在动态机械环境中起作用。细胞的机械调节在细胞的生长发育中起着重要的作用。 主动脉瓣钙化的发病机制。钙调蛋白2是一种肌钙蛋白样细胞骨架机械调节蛋白 在钙化的人体主动脉瓣中增加。在多种细胞类型中， 在CAVD中，我们将重点关注主动脉瓣间质细胞中Calponin 2的机械调节功能 在转分化成肌成纤维细胞和成骨细胞的过程中。这些研究将学习机械的见解 开发钙调蛋白2靶向治疗和预防瓣膜病背景下的CAVD 血液动力学和病理组织重塑。 本补充研究是在强有力的科学前提和前人研究的基础上提出的， 创新的分子靶点、可检验的假说和多层次的综合实验体系。的 预期的结果将具有重大的科学和医学意义。在钙调蛋白方面的专业知识 研究和CAVD专家的合作，我们富有成效的调查团队拥有所有必要的技术 能力、方法和工具以及小鼠模型，以启动新的研究并及时取得进展 开发一个更全面的研究计划，以转化为新的非手术治疗， 预防CAVD。