New Signaling Networks in Vascular Smooth Muscle

血管平滑肌中的新信号网络

基本信息

批准号：
10531647
负责人：
Zygmunt S Derewenda
金额：
$ 14.25万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531647
关键词：
Acute Address Agonist Animal Model Arteries Asthma Attenuated Blood Pressure Blood Vessels Blood capillaries Blood flow Comparative Study Data Development Disease Drug Targeting Dysbarism Functional disorder G-Protein-Coupled Receptors Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Health Hypertension Hypotension Knockout Mice Knowledge Mediating Mission Mus Muscle Contraction Muscle Tonus Myosin ATPase Myosin Light Chain Kinase Myosin Regulatory Light Chains NG-Nitroarginine Methyl Ester Nucleotides Outcome Pathologic Pathology Pathway interactions Patients Perfusion Pharmaceutical Preparations Pharmacology Phosphorylation Phosphotransferases Physiological Physiology Protein Dephosphorylation Protein Isoforms Public Health RPS6KA gene Regulation Relaxation Research Resistance Ribosomal Protein S6 Kinase Ribosomes Role Scheme Shock Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Testing Therapeutic Therapeutic Intervention United States National Institutes of Health Up-Regulation Vascular Smooth Muscle Vascular resistance Vasodilation Wild Type Mouse arteriole base blood pressure reduction blood pressure regulation cohort defined contribution hypertensive improved inhibitor knowledge base mechanical force myosin phosphatase new therapeutic target novel pressure response rho ribosomal protein S6 kinase kinase vasoconstriction

Acute Address Agonist Animal Model Arteries Asthma Attenuated Blood Pressure Blood Vessels Blood capillaries Blood flow Comparative Study Data Development Disease Drug Targeting Dysbarism Functional disorder G-Protein-Coupled Receptors Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Health Hypertension Hypotension Knockout Mice Knowledge Mediating Mission Mus Muscle Contraction Muscle Tonus Myosin ATPase Myosin Light Chain Kinase Myosin Regulatory Light Chains NG-Nitroarginine Methyl Ester Nucleotides Outcome Pathologic Pathology Pathway interactions Patients Perfusion Pharmaceutical Preparations Pharmacology Phosphorylation Phosphotransferases Physiological Physiology Protein Dephosphorylation Protein Isoforms Public Health RPS6KA gene Regulation Relaxation Research Resistance Ribosomal Protein S6 Kinase Ribosomes Role Scheme Shock Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Testing Therapeutic Therapeutic Intervention United States National Institutes of Health Up-Regulation Vascular Smooth Muscle Vascular resistance Vasodilation Wild Type Mouse arteriole base blood pressure reduction blood pressure regulation cohort defined contribution hypertensive improved inhibitor knowledge base mechanical force myosin phosphatase new therapeutic target novel pressure response rho ribosomal protein S6 kinase kinase vasoconstriction

展开

项目摘要

Abstract: This proposal focuses on our discovery of new signaling pathways mediated by the p90 ribosomal S6 kinase (RSK2) that regulate vascular smooth muscle (VSM) mediated vascular resistance, myogenic tone and blood flow with the rational that outcomes have potential to deliver new therapeutic targets. The myogenic response of small resistance arteries is critical for protection of downstream arterioles and capillaries against barotrauma due to excessive changes in intravascular pressure. Our understanding of the signaling pathways that control myogenic and agonist-mediated vasoconstriction, vascular resistance and blood pressure homeostasis are incomplete and this proposal addresses this gap in our knowledge base. Our overall objective is to determine the contribution of RSK2 to vascular physiology and pathophysiology from a mechanistic and functional perspective. Our central hypothesis is that RSK2 kinase mediates a novel network of pathways that result in regulation of VSM contraction in response to myogenic pressure and to agonists. This hypothesis is based on preliminary data identifying three RSK2 targets in resistance arteries which potentiate the contractile state: (1) RLC20, leading to direct augmentation of the canonical activation of myosin cross-bridge function; (2) NHE-1 Na+/H+ exchanger, the phosphorylation of which contributes to an increase in pHi associated with an increase in cytosolic [Ca2+], thereby potentiating the MLCK-mediated pathway; and (3) two RhoA-specific nucleotide exchange factors, with potential regulatory impact on the RhoA-mediated pathway. Our preliminary data also suggest that RSK2 signaling contributes ~20% of maximal myogenic force and that arteries from a Rsk2-/- mouse or treated with RSK inhibitors are more dilated, have reduced myogenic tone and RLC20 phosphorylation and that Rsk2-/- mice have lower blood pressure compared to wild-type mice. We hypothesize that this non-canonical RSK2 pathway augments and cross talks with the canonical Ca2+/MLCK and RhoA/ROCK Ca2+-sensitization pathways to regulate vasoconstriction and basal BP. The following aims test our hypotheses: Aim 1: To determine how RSK2 contributes to VSM contraction in response to perfusion pressure and agonists, with a focus on select phosphorylation targets, i.e. RLC20, NHE-1 and RhoGEFs. Aim 2: To assess the contribution of RSK2 to blood pressure homeostasis. Outcomes are expected to establish and add a new RSK2 mediated signaling network to the canonical MLCK and RhoA/ROCK signaling pathways regulating VSM tone and vasoconstriction and to provide possible new therapeutic targets for contractile pathologies of the vessel wall.

抽象的：该建议重点是我们发现由P90核糖体S6激酶介导的新信号通路（RSK2）调节血管平滑肌（VSM）介导的血管耐药性，肌原态和血液理性的结果是，结果有可能实现新的治疗靶标。肌源反应小型电阻动脉对于保护下游动脉和毛细血管免受Barotrauma至关重要至关重要过度变化血管内压。我们对控制的信号通路的理解肌原性和激动剂介导的血管收缩，血管抗性和血压稳态是不完整的，该提议在我们的知识基础上解决了这一差距。我们的总体目标是确定 RSK2对机械和功能的血管生理学和病理生理学的贡献看法。我们的中心假设是RSK2激酶介导了一种新的途径网络，导致响应肌源性压力和激动剂的VSM收缩调节。该假设基于在阻力动脉中识别三个RSK2靶标的初步数据，这些动脉增强了收缩状态：（1） RLC20，导致肌球蛋白跨桥功能的规范激活直接增强；（2）NHE-1 Na+/H+交换器，其磷酸化有助于与增加有关的PHI的增加在胞质[Ca2+]中，从而增强了MLCK介导的途径；（3）两个RhoA特异性核苷酸交换因子，对RhoA介导的途径的潜在调节影响。我们的初步数据提示RSK2信号传导占最大肌源力的约20％，并且来自RSK2 - / - 小鼠的动脉或用RSK抑制剂治疗的肿瘤抑制剂更加膨胀，肌源性张力降低和RLC20磷酸化和与野生型小鼠相比，RSK2 - / - 小鼠的血压较低。我们假设这种非经典性 RSK2途径增加并与规范CA2+/MLCK和Rhoa/Rock Ca2+ - 敏感调节血管收缩和基础BP的途径。以下目的测试我们的假设：目标1：确定RSK2如何响应灌注压力和激动剂对VSM收缩的贡献，专注于精选的磷酸化靶标，即RLC20，NHE-1和Rhogefs。目标2：评估 RSK2至血压稳态。结果有望建立并添加新的RSK2介导信号网络与规范MLCK和RHOA/ROCK信号通路调节VSM音调和血管收缩并为血管壁的收缩病理提供可能的新治疗靶标。