Signaling To and From the Vascular/Endothelial Compartment and Progression of HCM Linked to Sarcomere Mutations

往返于血管/内皮室的信号传导以及与肌节突变相关的 HCM 进展

• 批准号: 10598599
• 负责人: PAUL H GOLDSPINK
• 金额: $ 77.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598599
• 关键词: Agonist; Basic Science; Biochemical; Biophysics; Blood Vessels; Blood capillaries; Blood flow; Cardiovascular Diseases; Cells; Clinical; Clinical Research; Contractile Proteins; Coronary; Coronary artery; Cytoskeletal Proteins; Data; Defect; Development; Dimensions; Disease; Disease Progression; Early Intervention; Early identification; Endothelial Cells; Endothelium; Etiology; Excision; Extracellular Matrix; Female; Functional disorder; Generations; Genes; Genetic Diseases; Geometry; Heart; Histology; Hypertrophic Cardiomyopathy; Impairment; Intervention; Investigation; Ischemia; Knock-out; Knowledge; Link; Mediating; Mediator; Microfilaments; Modeling; Modification; Monitor; Mus; Muscle Cells; Mutation; Neonatal; Pathology; Pathway interactions; Population; Property; Proteins; Receptor Signaling; Regulation; Reporter; Reporting; RiboTag; Role; Sarcomeres; Signal Pathway; Signal Transduction; Testing; Therapeutic Intervention; Thin Filament; Time; Translational Regulation; Translations; Vascular Diseases; Vascular remodeling; coronary vasculature; coronary vasodilator; disease-causing mutation; effective therapy; endophenotype; experimental study; heart function; improved; individualized medicine; inorganic phosphate; male; mechanical signal; mechanotransduction; mouse model; novel; paracrine; prevent; protective effect; receptor; response; restoration; small molecule inhibitor; therapeutic target; translatome; vascular endothelial dysfunction

Project Summary/Abstract Hypertrophic cardiomyopathy (HCM) is a common familial cardiovascular disorder viewed as a genetic disease of the sarcomere, since most mutations occur in genes that encode sarcomere/cytoskeletal proteins. Despite decades of basic and clinical research, there are critical gaps in our knowledge concerning how defective biophysical signals in the myocyte influence the function of other cellular compartments of the heart during the clinical course of this disorder. We have reported that early interventions aimed at normalizing myofilament properties only partially prevent HCM progression. Moreover, removal of the triggering mutation does not always reverse progression. In experiments proposed here, we test the overall hypothesis that critical, but treatable, maladaptive modifications in the vascular/endothelial compartment occur early and in parallel with changes in myofilament properties in the progression of HCM linked to thin filament mutations triggering different biophysical and biochemical signals. Preliminary data strongly support a role for and a need to investigate vascular remodeling and endothelial dysfunction that exacerbate symptomatic HCM. Novel data support our focus on HIPPO/YAP/TAZ signaling with emphasis on protective effects of sphingsine-1-phosphate receptor (S1PR) signaling, which is common to the endothelium (EC) and myocytes (CM). Our aims are as follows: Aim 1. Determine the decline in coronary function, changes in vascular remodeling and mechano- sensing in HCM linked to mutationsTnT-R92Q and Tm-E180G with different signaling in progression to HCM. Aim 2. Establish whether restoration of the endothelial HIPPO pathway is sufficient to impede HCM progression. Evidence provided here for a role of EC HIPPO/YAP/TAZ signaling in HCM progression demands an investigation of the consequences of its regulation, and whether therapeutic interventions modify HIPPO signaling. Aim 3. Evaluate the microenvironmental signals responsible for HIPPO pathway dysregulation and co-translation expression of activated YAP/TAZ protective mediators in HCM. Our approach includes determination of the time course of changes in coronary flow velocity, vascular/endothelial histology, and mechano-sensing through key components of the HIPPO pathway, with changes in cardiac function and the myofilaments Ca2+-response during HCM progression. We will treat mouse models early in HCM progression with S1PR agonists, and small molecule inhibitors to normalize myofilament Ca2+ sensitivity and tension to examine whether they restore EC HIPPO pathway and angiogenic signaling. We will identity EC and CM specific disease signaling networks and determine whether HCM leads to impaired S1P export and paracrine function, by enriching and probing the "functional co-translatome" in the RiboTag reporter mice crossed with HCM mutations. Accomplishing our aims will provide discovery of targets for effective and individualized therapies for HCM.

项目摘要/摘要 肥厚心肌病（HCM）是一种常见的家族性心血管疾病，被视为遗传疾病 肌节的大多数突变发生在编码肉皮/细胞骨架蛋白的基因中。尽管 数十年的基础研究和临床研究，我们的知识存在关键的差距 肌细胞中的生物物理信号会影响心脏其他细胞室的功能 这种疾病的临床过程。我们报告说，旨在使肌膜正常化的早期干预措施 属性仅部分防止HCM进展。此外，去除触发突变不会 总是反向进展。在这里提出的实验中，我们检验了至关重要的总体假设 血管/内皮隔室中可治疗的，适应不良的修饰发生早期，并并行 与薄丝丝突变相关的HCM进展中肌丝特性的变化 不同的生物物理和生化信号。初步数据强烈支持角色和需要 研究恶性HCM的血管重塑和内皮功能障碍。新数据 支持我们对河马/Yap/taz信号的关注，重点是肝1-磷酸盐的保护作用 受体（S1PR）信号传导，这是内皮（EC）和心肌细胞（CM）共有的。我们的目标是 以下内容：目标1。确定冠状动脉功能下降，血管重塑的变化和机械 在HCM中的传感与MutationStnt-R92Q和TM-E180G相关联，在进展到HCM的信号传导不同。 目标2。确定内皮河马途径的恢复是否足以阻碍HCM 进展。这里提供的证据表明EC HIPPO/YAP/TAZ信号在HCM进展需求中的作用 调查其调节后果以及治疗干预措施是否修改河马 信号。目标3。评估负责河马途径失调和的微环境信号 HCM中活化的YAP/TAZ保护介质的共译表达。我们的方法包括 确定冠状动脉流速，血管/内皮组织学和 通过河马途径的关键组件进行机械感密度，心脏功能的变化和 HCM进展过程中的肌膜Ca2+反应。我们将在HCM进程中早期处理鼠标模型 用S1PR激动剂和小分子抑制剂使肌丝Ca2+敏感性和张力正常化为 检查它们是否恢复EC HIPPO途径和血管生成信号传导。我们将识别EC和CM 特定的疾病信号网络并确定HCM是否导致S1P出口和旁分泌受损 功能，通过在Ribotag报告中富集和探测与与 HCM突变。实现我们的目标将为有效和个性化的目标发现 HCM的疗法。