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.

补充研究总结 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塑和衰竭仍在继续，严重限制了 对长期生存的治疗效果。我们报道了编码钙调蛋白亚型的基因的敲除 2 减轻 ApoE 基因敲除小鼠中高氯血症引起的主动脉瓣钙化，这表明一种新的 治疗和预防 CAVD 的分子靶点。在这里我们建议扩大家长研究 该项目对钙调蛋白 2 在 CAVD 的发病机制和进展中的作用以及 发展非手术治疗和预防的基本机制。 进一步研究 Calponin 2 缺失或减少对减弱 CAVD 的发病机制和进展并了解其潜在的分子机制，我们应应用 综合多层次方法来实现两个补充的具体目标。目标 S1 是表征 钙调蛋白 2 缺失和减少对缓解 CAVD 的纵向益处以及有效性 不同病因的代表性小鼠模型。这些研究将调查疾病状态，其中 钙调蛋白2减少可有效预防、减轻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。主动脉 阀门在动态机械环境中发挥作用。细胞机械调节在 主动脉瓣钙化的发病机制。 Calponin 2 是一种肌钙蛋白样细胞骨架机械调节蛋白 在钙化的人主动脉瓣中增加。在涉及发病机制的多种细胞类型中 CAVD，我们将重点关注钙调蛋白2在主动脉瓣间质细胞中的机械调节功能的作用 在转分化为肌成纤维细胞和成骨细胞期间。这些研究将获得机制见解 开发瓣膜病背景下的钙调蛋白 2 靶向治疗和预防 CAVD 血流动力学和病理组织重塑。 这项补充研究是在强有力的科学前提和先前研究的基础上提出的， 创新的分子靶点、可检验的假设和多层次的综合实验系统。这 预期的结果将产生重大的科学和医学影响。凭借在钙调蛋白方面的专业知识 与 CAVD 专家合作进行研究，我们富有成效的研究团队拥有所有必要的技术 启动新研究并及时取得进展的能力、方法和工具以及小鼠模型 制定更全面的研究计划，以转化为新的非手术治疗方法 预防 CAVD。