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: 10444071
• 负责人: PAUL H GOLDSPINK
• 金额: $ 70.82万
• 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/10444071
• 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; 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 of activation protein; 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 Endothelium; 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.

项目总结/摘要 肥厚型心肌病（HCM）是一种常见的家族性心血管疾病，被认为是一种遗传性疾病 因为大多数突变发生在编码肌节/细胞骨架蛋白的基因中。尽管 经过几十年的基础和临床研究，我们对缺陷如何产生的认识存在重大空白。 心肌细胞中的生物物理信号影响心脏其他细胞区室的功能， 这种疾病的临床过程。我们已经报道了旨在使肌丝正常化的早期干预 这些特性仅部分阻止HCM进展。此外，去除触发突变并不 总是逆向发展。在这里提出的实验中，我们测试了整体假设，即关键的，但 可治疗的，适应不良的修改，在血管/内皮细胞室发生的早期和平行， HCM进展中肌丝特性的变化与细丝突变相关， 不同的生物物理和生物化学信号。初步数据有力地证明， 研究加重症状性HCM血管重塑和内皮功能障碍。新颖的数据 支持我们对HIPPO/雅普/TAZ信号转导的关注，重点是鞘氨醇-1-磷酸的保护作用 受体（S1 PR）信号传导，其为内皮细胞（EC）和肌细胞（CM）所共有。我们的目标是 目标1.确定冠状动脉功能的下降，血管重塑和机械性的变化， HCM中的传感与突变TnT-R92 Q和Tm-E180 G相关，在HCM进展中具有不同的信号传导。 目标2.确定内皮HIPPO通路的恢复是否足以阻止HCM 进展这里提供的证据表明EC HIPPO/雅普/TAZ信号在HCM进展需求中的作用 调查其调节的后果，以及治疗干预是否会改变HIPPO 信号目标3.评估导致HIPPO通路失调的微环境信号， HCM中激活的雅普/TAZ保护介质的共翻译表达。我们的方法包括 确定冠状动脉血流速度、血管/内皮组织学变化的时程，以及 通过HIPPO途径的关键成分进行机械感知，心脏功能和 肌丝Ca ~（2+）反应。我们将在HCM进展的早期治疗小鼠模型， 与S1 PR激动剂和小分子抑制剂一起使用，以使肌丝Ca 2+敏感性和张力正常化， 检查它们是否恢复EC HIPPO通路和血管生成信号传导。我们将识别EC和CM 特异性疾病信号网络，并确定HCM是否导致S1 P输出和旁分泌受损 功能，通过富集和探测RiboTag报告小鼠中的“功能性共翻译体”， HCM突变。实现我们的目标将提供有效的和个性化的目标发现 治疗HCM。