Structure-Function of Calcium Channel Complexes in Cardiac Physiology and Disease

钙通道复合物在心脏生理和疾病中的结构-功能

• 批准号: 10628911
• 负责人: Henry M. Colecraft
• 金额: $ 241.3万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628911
• 关键词: Address; Adrenergic Agents; Affect; Aging; Animal Model; Behavior; Calcium; Calcium Channel; Calcium Signaling; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cells; Chronic stress; Collaborations; Complex; Consanguinity; Coupling; DNA Sequence Alteration; Data; Development; Disease; Disease Progression; Dissection; Foundations; Functional disorder; Genotype; Goals; Health; Heart; Heart Diseases; Heart failure; Human; Individual; Knock-out; Knowledge; Link; Mediating; Missense Mutation; Molecular; Mus; Mutation; Myocardial dysfunction; Myocardium; Pakistan; Pathology; Pathway interactions; Phenotype; Physiological; Physiology; Population; Post-Translational Protein Processing; Prevalence; Program Research Project Grants; Proteins; Recording of previous events; Regulation; Regulatory Pathway; Research; Role; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Stress; Structure; Surface; United States; Variant; cohort; combat; effective therapy; experimental study; fighting; foot; genetic regulatory protein; genome resource; heart function; innovation; insight; loss of function mutation; nanobodies; nanoengineering; new therapeutic target; novel therapeutics; phenotypic data; prevent; receptor function; response; single molecule; structural biology; therapeutic target; tool; trafficking

SUMMARY Heart disease is the leading cause of death in the United States and worldwide, with a worsening trajectory due to increasingly aging populations. Precise understanding of the molecular mechanisms underlying normal cardiac physiology, and how they are compromised in disease, is critical for identifying new drug targets and developing effective new therapeutics to combat heart disease. Ca2+ cycling involving local signaling between surface L-type Ca2+ (CaV1.2) channels and intracellular ryanodine receptors (RYR2) is responsible for the Ca2+- induced Ca2+ release (CICR) that underlies cardiac excitation-contraction coupling. Dysregulation of both CaV1.2 and RYR2 contributes to abnormal calcium signaling that is an adverse hallmark of cardiac disease. β-adrenergic augmentation of cardiac contractility is crucial for the fight-or-flight response and is mediated by increased CaV1.2 current and sensitization of RYR2; yet, excessive activation of this pathway under chronic stress results in post- translational modifications of RYR2 channels that cause them to become ‘leaky’ and cause cardiac pathology, and also a potential harmful subcellular redistribution of CaV1.2. There are significant gaps in knowledge regarding CaV1.2 and RYR2 functional organization and regulation in heart under both and disease conditions; how their dysregulation or dysfunction contributes to heart disease progression; and whether and how they can be targeted for effective treatment of heart failure (HF) and other cardiac diseases. This Program Project Grant (PPG) comprises four Projects and two Scientific Cores that have been put together to help address these critical gaps. The overarching goal is to define the mechanisms that regulate local Ca2+ signaling by CaV1.2 and RYR2 in normal and failing hearts with unprecedented precision. While each project stands on its own footing as far as being comprised of innovative and exciting research, all are dependent on the expertise provided by the Cores and are enriched by interproject collaborations that are greatly enhanced by the PPG structure. All four Projects leverage the Pakistan Genome Resource (PGR) (Core A), a unique cohort of individuals with extensive phenotype and genotype data on HF and other cardiac diseases and high rates of consanguinity enabling identification of individuals homozygous for rare truncating mutations (i.e., human knockouts) and other missense variants. Moreover, all four Projects involve experiments that span fundamental studies on single molecules and cells to animal models (Core B; Mouse Cardiac Physiology Core). Combining human missense / loss of function mutations found in the PGR cohort in CaV1.2, RYR2 or key regulatory proteins with in-depth structure-function experiments promises to advance new understanding of genotype-phenotype relationships in human cardiovascular diseases involving Ca2+ cycling proteins in the heart. We expect the proposed studies to yield new insights into structure-function and regulation of CaV1.2 and RYR2 and advance their utility as therapeutic targets for cardiac dysfunction. The PIs of the four projects have a collaboration history and track record of developing innovative approaches for studies of CaV1.2 and RYR2 molecular physiology.

概括 心脏病是美国和全球死亡的主要原因，并有令人担忧的轨迹 越来越老化的人口。精确理解正常的分子机制 心脏生理及其在疾病中如何妥协，对于识别新药物靶标和 开发有效的新疗法来打击心脏病。 CA2+骑自行车涉及局部信号 表面L型Ca2+（Cav1.2）通道和细胞内瑞氨烷受体（RYR2）负责Ca2+ - 诱导的Ca2+释放（CICR）是心脏兴奋 - 收缩耦合的基础。两个CAV1.2的失调 RYR2有助于异常的钙信号传导，这是心脏病的不利标志。 β-肾上腺素 心脏收缩性的增强对于战斗或飞行的反应至关重要，CAV1.2介导 RYR2的电流和灵敏度；然而，在慢性应激下，该途径过多激活导致 RYR2通道的翻译修饰会导致它们变得“漏水”并引起心脏病理， 以及Cav1.2的潜在有害亚细胞重新分布。知识中有很大的差距 关于CAV1.2和RYR2功能组织以及在疾病条件下心脏的调节； 它们的功能障碍或功能障碍如何导致心脏病进展；以及他们如何以及如何 针对有效治疗心力衰竭（HF）和其他心脏病。该计划项目赠款 （PPG）由四个项目和两个科学核心组成，这些项目被整理在一起，以帮助解决这些关键 空白。总体目标是定义通过CAV1.2和RYR2调节局部Ca2+信号的机制 在正常和失败的心中，精度前所未有。每个项目都站在自己的立足点 完成创新和令人兴奋的研究，所有这些都取决于核心提供的专业知识 并由PPG结构大大增强的室间协作丰富。所有四个项目 利用巴基斯坦基因组资源（PGR）（核心A），这是一个独特的人群 有关HF和其他心脏病的表型和基因型数据以及较高的血统率 识别纯合的个体，用于罕见的截断突变（即人敲除）和其他 错义变体。此外，这四个项目均涉及实验，这些实验涵盖了单一的基础研究 分子和细胞到动物模型（核心B；小鼠心脏生理核心）。结合人类的错义 / 在cav1.2，ryR2或密钥调节蛋白中发现的功能突变损失，深度为 结构功能实验有望提高对基因型 - 表型关系的新理解 人的心血管疾病涉及心脏中的Ca2+循环蛋白。我们希望拟议的研究能够 对CAV1.2和RYR2的结构功能和调节产生新的见解，并推进其实用性 心脏功能障碍的治疗靶标。这四个项目的PI具有协作历史和跟踪 开发用于CAV1.2和RYR2分子生理研究的创新方法的记录。