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: 8523415
• 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/8523415
• 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.

描述（由申请人提供）：心肌肌球蛋白结合蛋白-C 对健康和衰竭心脏候选者的贡献摘要。我是一名心脏病专家，从第二年开始在德克萨斯 A&M 健康科学中心 (HSC) 医学院担任助理教授。我相信我的使命是进行有助于心力衰竭治疗的研究，并直接参与心力衰竭患者的治疗。尽管我接受了良好的科学研究教育，但长达 7 年的专业临床培训阻碍了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、发表重要发现以及获得 NIH R01 级资金以继续向独立研究者发展。该指导性研究职业发展奖（K08）提供了实现这些过渡目标的方法。研究。我将重点阐明心肌肌球蛋白结合蛋白 C (MyBPC3) 对健康和衰竭心脏的贡献。一名 40 岁的美国人一生中患心力衰竭 (HF) 的风险为 20%。射血分数保留的心力衰竭 (HFpEF) 目前尚无有效的治疗方法，其患病率已增加至所有心力衰竭病例的约 50%。粗丝肌球蛋白跨桥附着于细丝上的肌动蛋白，将储存的化学能转化为力，然后分离的循环形成了心脏收缩和舒张的基础。 MyBPC3 抑制与肌动蛋白的跨桥相互作用。 MyBPC3 的磷酸化可能会释放其抑制作用，从而促进跨桥循环。因此，我假设 MyBPC3 磷酸化调节跨桥循环以增强收缩性（产生力的能力）和松弛性（放松的能力）。 我将通过使用转基因小鼠模型来阐明 MyBPC3 的存在和磷酸化对心脏功能的影响。 MyBPC3 的存在和磷酸化的控制是通过分别在 MyBPC3(- /-) 背景上删除 MyBPC3 基因和表达磷酸化模拟 MyBPC3 突变体来实现的。初步数据强烈表明，MyBPC3 缺失会导致射血分数降低的心力衰竭 (HFrEF)，而 MyBPC3 磷酸化缺陷会导致 HFpEF。 我还将确定使用 MyBPC3 磷酸化来预防和治疗 HFpEF 的能力。治疗理念集中于这样一种可能性：MyBPC3 磷酸化介导的收缩性和松弛性增强将维持足够的心脏功能，而无需在应激期间出现肥厚反应。将通过挑战组成型磷酸化 MyBPC3 小鼠模型来测试预防措施，该模型具有通常会导致舒张功能障碍的压力。通过病毒基因转移诱导磷酸化 MyBPC3 模拟物的表达以及应激期间诱导的基因表达将决定治疗潜力。职业发展。来自全国各地的专家团队已集结提供指导。该团队由 Solaro 博士（跨桥自行车细丝调节领域的领先专家、初级 导师）、Moss 博士（MyBPC3 和跨桥自行车粗丝调节领域的领先专家）和 Redfield 博士（HFpEF 领域的权威和大型动物模型专家）。此外，Hajjar 博士（使用病毒基因转移治疗心力衰竭的领先专家）将作为 病毒载体构建顾问。德克萨斯农工大学团队的一部分将提供机构支持和现场专业知识的保证。我将学习压力量的新技能 循环测量来确认 HFpEF，二维荧光差异凝胶电泳来识别 MyBPC3 的翻译后修饰，应激技术诱导小鼠舒张功能障碍，病毒基因转移与诱导基因表达相辅相成，以测试靶向 MyBPC3 磷酸化作为潜在的治疗方法。通过这个过程，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，指导团队还将就成果发表和NIH研究项目补助金（R01）的准备提供指导。环境。我的主要任命是在系统生物学和转化医学（SBTM）基础科学系工作。 SBTM 部门培养了独立调查员，他们后来担任学术机构的主席。启动包提供了设备采购和实验室空间。 SBTM 和 Texas A&M HSC 都有不同级别的调查员，他们具备技能并且热衷于合作。德克萨斯 A&M HSC 保证在 5 年内将 75% 的精力投入到这项研究中，无论是否获得 K08 奖励资金。此外，Texas A&M HSC 已同意退还 K08 奖项产生的所有工资节省；因此，该协议对K08奖励产生倍增效应。因此，我生活在一个非常适合作为独立调查员发展的环境中。概括。完成这些拟议的研究将提供新的技能、资源和发现。因此，资助该提案将有助于解决令人烦恼的健康问题，并使刚起步的临床科学家能够走上独立研究的道路。