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.

项目概要/摘要 肥厚型心肌病 (HCM) 是一种常见的家族性心血管疾病，被视为遗传性疾病 肌节，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 经过数十年的基础和临床研究，我们对缺陷的认识存在严重差距 心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。我们报道了旨在使肌丝正常化的早期干预措施 特性只能部分阻止 HCM 进展。此外，去除触发突变并不 总是逆转进展。在这里提出的实验中，我们测试了关键的总体假设，但是 血管/内皮室中可治疗的、适应不良的改变发生得很早，并且与 HCM 进展过程中肌丝特性的变化与细丝突变触发相关 不同的生物物理和生化信号。初步数据有力地支持了这一作用和必要性 研究加剧 HCM 症状的血管重塑和内皮功能障碍。新颖的数据 支持我们对 HIPPO/YAP/TAZ 信号传导的关注，重点关注 1-磷酸鞘氨醇的保护作用 受体 (S1PR) 信号传导，这是内皮细胞 (EC) 和肌细胞 (CM) 所共有的。我们的目标是 目标 1. 确定冠状动脉功能的下降、血管重塑和力学变化 HCM 中的传感与 TnT-R92Q 和 Tm-E180G 突变相关，在 HCM 进展过程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。这里提供了 EC HIPPO/YAP/TAZ 信号在 HCM 进展需求中的作用的证据 对其调节后果的调查，以及治疗干预是否会改变 HIPPO 发信号。目标 3. 评估导致 HIPPO 通路失调的微环境信号和 HCM 中激活的 YAP/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间过程，以及 通过 HIPPO 通路的关键组成部分进行机械传感，改变心脏功能和 HCM 进展期间肌丝 Ca2+ 反应。我们将在 HCM 进展早期治疗小鼠模型 使用 S1PR 激动剂和小分子抑制剂使肌丝 Ca2+ 敏感性和张力正常化 检查它们是否恢复 EC HIPPO 通路和血管生成信号。我们将识别EC和CM 特定疾病信号网络并确定 HCM 是否导致 S1P 输出和旁分泌受损 通过丰富和探索与 RiboTag 报告小鼠杂交的“功能性共翻译组” HCM 突变。实现我们的目标将为有效和个性化的目标提供发现 HCM 的治疗方法。