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(申请人提供)：心肌肌球蛋白结合蛋白-C对健康和衰竭的候选心脏的贡献摘要。我是一名心脏病专家，从第二年开始在德克萨斯农工大学健康科学中心(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。虽然我在科研方面接受了很好的教育，但总共7年的专业临床培训暂停了我作为一名独立研究人员的发展。因此，我的短期过渡目标包括获得新的技能，开发资源，发表重要发现，并获得NIH R01水平的资金，以继续向独立研究人员发展。这项指导研究职业发展奖(K08)提供了实现这些过渡目标的手段。研究。我将集中阐述心肌肌球蛋白结合蛋白-C(MYBPC3)对健康和衰竭心脏的作用。一名40岁的美国人一生中罹患心力衰竭(HF)的风险为20%。射血分数(HFpEF)保留的心力衰竭(HF)目前尚无有效的治疗方法，但其患病率已上升至约50%。粗丝肌球蛋白跨桥连接到细丝上的肌动蛋白，将储存的化学能转化为力，然后分离，形成心脏收缩和松弛的基础。MYBPC3抑制与肌动蛋白的跨桥相互作用。MYBPC3的磷酸化可能释放其抑制作用，促进跨桥循环。因此，我假设MYBPC3的磷酸化调节了跨桥循环，以增强收缩能力(产生力量的能力)和松弛能力(放松能力)。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基因的缺失和MYBPC3的磷酸化模拟突变体分别在MYBPC3(-/-)背景上表达，从而控制MYBPC3的存在和磷酸化。初步数据有力地表明，MYBPC3缺失导致射血分数(HFrEF)降低的心衰，MYBPC3磷酸化缺陷导致HFpEF。我还将确定使用MYBPC3磷酸化来预防和治疗HFpEF的能力。治疗思想集中在MYBPC3磷酸化介导的收缩和肌力增强将在应激期间维持足够的心功能而不需要肥大反应的可能性。预防将通过挑战构成磷酸化的MYBPC3小鼠模型进行测试，应激通常会导致舒张期功能障碍。通过病毒基因转移诱导磷酸化的MYBPC3模拟物的表达，以及在胁迫过程中诱导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经聚集在一起，提供指导。该团队由Solaro博士(跨桥自行车细纤维调节方面的领先专家，初级 Mentor)、Moss博士(MYBPC3和跨桥自行车粗丝调控方面的领先专家)和Redfield博士(HFpEF方面的领先权威和大型动物模型专家)。此外，Hajjar博士(使用病毒基因转移进行HF治疗的领先专家)将作为 病毒载体构建的顾问。团队中的德克萨斯A&M部分将提供机构支持和现场专业知识的保证。我要学习新的压力-音量技巧 循环测量以确认HFpEF，二维荧光差异凝胶电泳法确定MYBPC3的翻译后修饰，应激技术诱导小鼠舒张期功能障碍，以及病毒基因转移与诱导基因表达互补以测试靶向MYBPC3磷酸化作为潜在的治疗方法。通过这一过程，我将开发新的病毒基因转移载体资源和诱导基因表达构建。此外，指导小组还将就发表结果和准备国家卫生研究院研究项目补助金提供指导(R01)。环境我的主要职位是系统生物学和转化医学(SBTM)基础科学系。SBTM部门已经产生了独立的调查人员，他们后来担任了学术机构的主席。创业包提供了购买设备和实验室的空间。SBTM和德克萨斯A&M HSC都有不同级别的调查人员，他们拥有技能，并热衷于合作。德克萨斯A&M HSC已保证受保护的75%致力于这项研究的工作为期5年，独立于K08奖励资金。此外，德克萨斯A&M HSC已同意退还K08奖励产生的所有节省的工资；因此，本协议对K08奖励提供了乘数效应。因此，我生活在一个很好的环境中，可以发展成为一名独立的调查员。总结。完成这些拟议的研究将提供新的技能、资源和发现。因此，资助这项建议将有助于解决一个令人烦恼的健康问题，并使初级临床医生科学家能够走向独立研究的道路。