Dissecting the role of novel calcium regulatory proteins in the cardiovascular system

剖析新型钙调节蛋白在心血管系统中的作用

• 批准号: 10055197
• 负责人: Catherine A Makarewich
• 金额: $ 24.9万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055197
• 关键词: Animals; Apoptosis; Award; Biological; Blood Vessels; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular system; Cause of Death; Cell physiology; Characteristics; Companions; Complex; Developed Countries; Developing Countries; Development; Diet; Dilated Cardiomyopathy; Disease; Down-Regulation; Dwarfism; Endoplasmic Reticulum; Endothelial Cells; Energy Metabolism; Etiology; Event; Family; Foundations; Functional disorder; Gene Combinations; Gene Delivery; Genes; Genetic; Health; Heart; Heart failure; High Fat Diet; Homeostasis; Impairment; In Vitro; Ions; Knockout Mice; Knowledge; Malignant Neoplasms; Mediating; Mentors; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Modeling; Molecular; Mus; Muscle Cells; Muscle Contraction; Nodal; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Open Reading Frames; Pathway interactions; Patients; Peptides; Phase; Phenotype; Physiological; Physiological Processes; Play; Prevalence; Procedures; Proteins; Pump; Regulation; Research; Resistance; Reticulum; Role; Science; Scientist; Second Messenger Systems; Site; Smooth Muscle Myocytes; Stress; Supervision; Techniques; Testing; Therapeutic; Time; Tissues; Training; Transgenes; cardiovascular disorder therapy; career; cell type; design; disability; effective therapy; experience; genetic regulatory protein; heart function; in vivo; inhibitor/antagonist; insight; loss of function; mouse model; novel; novel therapeutics; overexpression; phospholamban; programs; sarcolipin; sarcoplasmic reticulum calcium ATPase; skills; success; symptom treatment; treatment strategy

Project Summary Cardiovascular disease (CVD) is the leading cause of death in the world. Current therapies for CVD aim to treat the symptoms rather than the underlying cause of the disease, thus we desperately need novel insights into the molecular mechanisms of CVD to develop new therapies. Calcium (Ca2+) ions play critical roles in fundamental physiological processes in the cardiovascular system that underlie tissue homeostasis and pump function. A universal characteristic of the failing heart is impaired Ca2+ cycling through the sarco/endoplasmic reticulum (S/ER), the major internal store of Ca2+ in cardiomyocytes. Ca2+ re-sequestration into the S/ER is mediated by a Ca2+-ATPase pump (SERCA), whose activity is regulated by phospholamban (PLN) and sarcolipin (SLN). In the past 3 years, we have identified 4 additional conserved small proteins that regulate SERCA activity in myocytes and non-myocyte cell types, consisting of myoregulin (MLN), endoregulin (ELN), anotheregulin (ALN) and dwarf open reading frame (DWORF). This proposal outlines a comprehensive plan to dissect the function of these peptides to provide critical insights into the complex mechanism of SERCA regulation and Ca2+ homeostasis. To accomplish this, I will employ the following 3 specific aims: 1. To examine the role of ELN and ALN as nodal regulators of SERCA activity, 2. To analyze the in vivo function of the cardiac expressed SERCA-regulins in health and disease, and 3. To investigate the role of Ca2+ dysregulation and SERCA dysfunction in the development of metabolic disorders and cardiovascular disease. The K99 portion of this proposal will be carried out in the lab of the renowned molecular biologist, Dr. Eric Olson. Under Dr. Olson’s guidance, I will functionally characterize the phenotype of ALN and ELN loss-of-function mice and elucidate their mechanism of action (Aim 1). Aims 2a and 2b, which are dedicated to characterizing the cardiomyocyte expressed peptides (ALN, PLN and DWORF), will be initiated under Dr. Olson’s supervision and continued during the independent phase. Finally, the techniques to evaluate systemic metabolism detailed in Aim 3 represent new research experiences for me and will require extensive training during the K99 phase of my award. The knowledge and skills that I acquire during this time will serve as critical components of the foundation of my own independent lab. In summary, the comprehensive plan proposed in this Pathway to Independence Award application will provide me with the opportunity to continue to develop an independent research program that will be instrumental in my success as a scientist. Importantly, the collective body of work generated through the completion of the proposed Aims will make major contributions to the field of cardiovascular science and will set the tone for my career.

项目摘要 心血管疾病（CVD）是世界上死亡的主要原因。 CVD目前的治疗疗法 症状而不是疾病的根本原因，因此我们迫切需要对 CVD开发新疗法的分子机制。钙（Ca2+）离子在基本中起关键作用 基于组织稳态和泵功能的心血管系统中的生理过程。一个 失败的心脏的普遍特征受到CA2+骑自行车的肌肉/内质网 （S/er），心肌细胞中Ca2+的主要内部存储。 Ca2+将重新测试置于S/ER中是由A介导的 Ca2+-ATPase Pump（SERCA），其活性受磷脂（PLN）和萨科利宾（SLN）的调节。在 在过去的3年中，我们已经确定了4种构成调节肌细胞中SERCA活性的小蛋白 和非肌细胞细胞类型，由肌酸蛋白（MLN），内龙蛋白（ELN），另一种常规蛋白（ALN）和矮人组成 开放阅读框（Dworf）。该提案概述了剖析这些功能的全面计划 肽可提供有关SERCA调节和Ca2+稳态的复杂机制的关键见解。 为此，我将采用以下3个特定目标：1。检查ELN和ALN作为节点的作用 SERCA活性的调节剂，2。分析心脏表达的SERCA-Regulins的体内功能 健康与疾病，以及3。 代谢疾病和心血管疾病的发展。该提案的K99部分将被携带 在著名的分子生物学家埃里克·奥尔森（Eric Olson）博士的实验室中。在奥尔森博士的指导下，我将在功能上 表征ALN和ELN功能丧失小鼠的表型并阐明其作用机理（AIM 1）。 AIMS 2A和2B，致力于表征心肌细胞表达的肽（ALN，PLN） 和Dworf）将在Olson博士的监督下启动，并在独立阶段继续。 最后，评估AIM 3中详细介绍的系统新陈代谢的技术代表了新的研究经验 对我而言，将需要在我奖励的K99阶段进行广泛的培训。我的知识和技能 在此期间获得的收购将是我自己独立实验室基础的关键组成部分。 总而言之，在本独立奖申请途径中提出的全面计划将提供 我有机会继续制定一个独立的研究计划，这将在我的 作为科学家的成功。重要的是，通过拟议的完成产生的集体工作机构 目标将为心血管科学领域做出重大贡献，并为我的职业生涯定下基调。