Contributions of Cardiac Myosin Binding Protein-C to Healthy and Failing Hearts

心肌肌球蛋白结合蛋白 C 对健康和衰竭心脏的贡献

• 批准号: 8353843
• 负责人: Carl Wei-Chan Tong
• 金额: $ 12.47万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353843
• 关键词: Abbreviations; Acceleration; Acetates; Actins; Affect; Agreement; American; Animal Model; Appointment; Award; Basic Science; Body Weight; Calcium; Cardiac; Cardiac Myosins; Chemicals; Clinical; Contracts; Country; Data; Deoxycorticosterone; Development; EFRAC; Echocardiography; Education; Ensure; Environment; Equipment; Fluorescence; Functional disorder; Funding; Gene Expression; Gene Transfer; Goals; Health; Health Sciences; Heart; Heart failure; Human; Hypertension; Hypertrophy; Institution; Interruption; K-Series Research Career Programs; Knock-out; Knowledge; Laboratories; Learning; Life; Lung; Measurement; Measures; Mediating; Medicine; Mentors; Methods; Mind; Modification; Mosses; Motor; Mus; Myocardium; Myosin ATPase; Nephrectomy; Normal Range; Patients; Pattern; Phosphorylation; Preparation; Prevalence; Prevention; Process; Proteins; Publications; Publishing; Recombinant adeno-associated virus (rAAV); Regulation; Relaxation; Research; Research Personnel; Research Project Grants; Resources; Rest; Risk; Running; Savings; Scientist; Severities; Speed; Stress; Systems Biology; Techniques; Testing; Texas; Therapeutic; Thick Filament; Thin Filament; Time; Training; Translating; Translations; United States National Institutes of Health; Viral Genes; Virus; Wages; Wild Type Mouse; abstracting; authority; base; career development; college; cost; effective therapy; gel electrophoresis; gene transfer vector; heart function; killings; mimetics; mouse model; mutant; myosin-binding protein C; papillary muscle; pressure; prevent; professor; response; skills; translational medicine; two-dimensional; vector

DESCRIPTION (provided by applicant): Abstract for Contributions of cardiac myosin binding protein-C to healthy and failing hearts Candidate. I am a cardiologist starting 2nd year as an assistant professor at Texas A&M Health Science Center (HSC) College of Medicine. I believe that my calling is to conduct research that can contribute to treatment of heart failure and directly participate in treatment of heart failure patients. Although I've received excellent education in scientific research, 7 total years of required dedicated clinical training has paused my development as an independent investigator. Thus, my short term transitional goals consist of acquiring new skills, developing resources, publishing important findings, and obtaining NIH R01 level funding to continue development toward independent investigator. This mentored research career development award (K08) provides the means to achieve these transitional goals. Research. I will focus on elucidating contributions of cardiac myosin binding protein-C (MyBPC3) to healthy and failing hearts. A 40 year old American has 20% life-time risk of developing heart failure (HF). HF with preserved ejection fraction (HFpEF), which there is no effective treatment, has increased prevalence to ~50% of all HF cases. The cycle of thick filament myosin cross-bridge attaching to actin on the thin filament, converting stored chemical energy to force, and then detaching forms the basis for contraction and relaxation of heart. MyBPC3 inhibits cross-bridge interaction with actin. Phosphorylation of MyBPC3 may release its inhibition to promote cross-bridge cycling. Thus, I hypothesize that MyBPC3 phosphorylation regulates cross- bridge cycling to enhance both contractility (ability to generate force) and lusitropy (ability to relax). I will elucidate the effects of presence and phosphorylation of MyBPC3 on heart function through the use genetically modified mouse models. Control of presence and phosphorylation of MyBPC3 is achieved through deletion of MyBPC3 gene and expression of phosphorylation mimetic MyBPC3 mutants on MyBPC3(- /-) background respectively. Preliminary data strongly suggests that MyBPC3 deletion leads to HF with reduced ejection fraction (HFrEF) and MyBPC3 phosphorylation deficiency leads to HFpEF. I will also determine the ability of using MyBPC3 phosphorylation to prevent and treat HFpEF. Therapeutic idea centers on the possibility that MyBPC3 phosphorylation mediated enhancements of contractility and lusitropy will maintain sufficient cardiac function without needing hypertrophic response during stress. Prevention will be tested through challenging constitutively phosphorylated MyBPC3 mouse model with stress that normally causes diastolic dysfunction. Inducing expression of phosphorylated MyBPC3 mimetic through viral gene transfer and induced gene expression during stress will determine treatment potential. Career Development. An expert team from across the country has assembled to provide mentoring. The team consists of Dr. Solaro (leading expert in thin filament regulation of cross-bridge cycling, primary mentor), Dr. Moss (leading expert in MyBPC3 and thick filament regulation of cross-bridge cycling), and Dr. Redfield (leading authority on HFpEF and expert in large animal models). In addition, Dr. Hajjar (leading expert in using viral gene transfer for HF therapy), will assist as a consultant on construction of virus vectors. Texas A&M portion of the team will provide assurance of institutional support and onsite expertise. I will learn new skills of pressure-volume loop measurements to confirm HFpEF, 2-dimensional fluorescence difference gel electrophoresis to identify post-translation modifications on MyBPC3, stress technique to induce diastolic dysfunction in mice, and viral gene transfer in compliment to inducible gene expression to test targeted MyBPC3 phosphorylation as potential treatment. Through the process, I will have developed new resources of viral gene transfer vector and inducible gene expression construct. Furthermore, the mentoring team will also provide guidance on publication of results and preparation of NIH research project grant (R01). Environment. My primary appointment is with basic science department of system biology and translational medicine (SBTM). The SBTM department has produced independent investigators that went on to hold chairmanships at academic institutions. Start-up package has provided equipment purchases and laboratory space. Both SBTM and Texas A&M HSC have investigators at various levels who have the skills and are enthusiastic to collaborate. Texas A&M HSC has guaranteed protected 75% effort dedicated to this research for 5-years independent of receiving K08 award funding. Furthermore, Texas A&M HSC has agreed to return all salary savings generated from K08 award; therefore, this agreement provides a multiplication effect on the K08 award. Thus, I reside in an excellent environment to develop as an independent investigator. Summary. Accomplishing these proposed studies will provide new skills, resources, and discoveries. Thus, funding this proposal will help to solve a vexing health problem and enable a beginning clinician scientist toward path of independent research. PUBLIC HEALTH RELEVANCE: A 40-year old American has 1 in 5 chance of developing heart failure during rest of his/her life. Heart failure kills 50% of its victims in 5 years. Cardic myosin binding protein-C (MyBPC3) is a component of the heart muscle. MyBPC3 regulates the speed of motor-like proteins that cause the heart to contract and relax with each beat. This project seeks to understand how MyBPC3 malfunction can cause heart failure. Furthermore, this project will determine the ability of using modified form of MyBPC3 to prevent and treat heart failure.

描述（由申请人提供）：摘要，摘要心脏肌球蛋白结合蛋白-C对健康和失败的心脏候选者的贡献。我是第二年的心脏病专家，在德克萨斯A＆M健康科学中心（HSC）医学院担任助理教授。我相信我的呼吁是进行可以有助于治疗心力衰竭并直接参与心力衰竭患者的研究。尽管我在科学研究方面接受了出色的教育，但总共需要7年的专门临床培训来暂停我作为独立研究者的发展。因此，我的短期过渡目标包括获取新技能，开发资源，发布重要发现以及获得NIH R01级资金，以继续向独立研究者发展。这项指导的研究职业发展奖（K08）提供了实现这些过渡目标的手段。研究。我将专注于阐明心脏肌球蛋白结合蛋白-C（MYBPC3）对健康和失败的心脏的贡献。一名40岁的美国人患心力衰竭（HF）的终生风险为20％。没有有效治疗的HF具有保留的射血分数（HFPEF），其患病率增加到所有HF病例的50％。厚丝肌球蛋白跨桥的循环连接到肌动蛋白上的细丝上，将存储的化学能转换为力，然后脱离为心脏收缩和放松的基础。 MYBPC3抑制肌动蛋白的跨桥相互作用。 MYBPC3的磷酸化可能会释放其抑制跨桥循环的抑制作用。因此，我假设MYBPC3磷酸化调节跨桥循环以增强收缩力（产生力的能力）和lusitropy（放松的能力）。 我将通过使用转基因的小鼠模型来阐明MYBPC3对心脏功能的存在和磷酸化的影响。通过删除MYBPC3基因和磷酸化模拟MYBPC3突变体在MyBPC3（ - / - ）背景上，通过缺失和磷酸化模拟MYBPC3突变体的表达来控制MYBPC3的存在和磷酸化。初步数据强烈表明MYBPC3缺失导致HF，射血分数（HFREF）降低，MYBPC3磷酸化缺乏导致HFPEF。 我还将确定使用MYBPC3磷酸化预防和治疗HFPEF的能力。治疗想法集中在MyBPC3磷酸化介导的收缩力和lusitrepony的增强的可能性中，将保持足够的心脏功能，而无需在压力期间需要肥大反应。预防将通过具有挑战性的组成性磷酸化MYBPC3小鼠模型进行测试，该模型通常会引起舒张功能障碍。通过病毒基因转移诱导磷酸化的MyBPC3表达表达和在压力期间诱导基因表达的表达将确定治疗潜力。职业发展。来自全国各地的专家团队已经组装了指导。该团队由Solaro博士组成（Solaro博士（跨桥骑自行车的薄丝细丝法规，主要专家 Mentor），Moss博士（MYBPC3和Cross-Bridge骑行的厚细丝监管的领先专家）和Redfield博士（HFPEF的领先权力和大型动物模型的专家）。此外，Hajjar博士（使用病毒基因转移进行HF疗法的领先专家）将有助于作为 病毒载体建设的顾问。该团队的德克萨斯A＆M部分将提供机构支持和现场专业知识的保证。我将学习压力卷的新技能 循环测量以确认HFPEF，二维荧光差凝胶电泳，以鉴定对MYBPC3上的翻译后修饰，诱导小鼠中舒张性功能障碍的压力技术以及在成熟中的病毒基因转移以诱导基因表达以测试靶向靶向的MYBPC3磷酸化的潜在治疗方法。通过这一过程，我将开发出病毒基因转移载体和诱导基因表达构建体的新资源。此外，指导团队还将为发布结果和NIH研究项目赠款的准备（R01）提供指导。环境。我的主要任命是在系统生物学和转化医学基础科学系（SBTM）任命。 SBTM部门培养了独立调查员，该研究人员继续在学术机构担任主席。启动套餐提供了设备购买和实验室空间。 SBTM和Texas A＆M HSC都有各个级别的调查员，他们具有技能并热情地合作。德克萨斯州A＆M HSC已保证为这项研究提供了75％的努力，该研究五年独立于获得K08奖励资金。此外，德克萨斯州A＆M HSC已同意退还来自K08奖产生的所有薪水；因此，本协议对K08奖励产生了乘法效果。因此，我居住在一个很棒的环境中，以发展为独立研究者。概括。完成这些建议的研究将提供新的技能，资源和发现。因此，为此提案提供资金将有助于解决一个令人沮丧的健康问题，并使初学者的科学家能够走向独立研究的道路。 公共卫生相关性：一名40岁的美国人在其余生中有五分之一的机会出现心力衰竭。心力衰竭在5年内杀死了50％的受害者。 Cardic肌球蛋白结合蛋白-C（MYBPC3）是心肌的组成部分。 MYBPC3调节运动状蛋白的速度，这会导致心脏收缩并在每次节拍中放松。该项目试图了解MYBPC3故障如何导致心力衰竭。此外，该项目将确定使用MYBPC3修改形式预防和治疗心力衰竭的能力。