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Physiological Role of Activation of the JAK/STAT pathway in Hypertension

JAK/STAT 通路激活在高血压中的生理作用

基本信息

批准号：
7530478
负责人：
Amy Banes-Berceli
金额：
$ 9万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-08 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7530478
关键词：
1-Phosphatidylinositol 3-Kinase ANG gene Angiotensin II Animals Biochemical Blood Pressure Blood Vessels Calcium Channel Clinical Cyclic AMP-Dependent Protein Kinases Cytokine Inducible SH2-Containing Protein DOCA Data Development Diabetes Mellitus Disease Disease Progression Endothelin-1 Event Excretory function Extracellular Matrix Proteins Functional disorder Genetic Transcription Glomerular Mesangial Cell Goals Growth Growth Factor Healthcare Systems Hyperglycemia Hypertension In Vitro Infusion procedures Inositol Insulin-Dependent Diabetes Mellitus Intervention JAK2 gene Janus kinase Janus kinase 1 Kidney Kidney Diseases L-Type Calcium Channels Laboratory Research MCC protocol Mentors Modeling Molecular Norepinephrine Organ PTPN1 gene PTPN11 gene PTPN6 gene Pathologic Processes Pathway interactions Patients Phase Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphotransferases Physiological Physiology Protein Kinase C Proteins Proteinuria Quality of life Rate Regulation Renal Blood Flow Reporting Rho-associated kinase Role Signal Pathway Signal Transduction Smooth Muscle Myocytes Sodium Sodium Chloride Testing Transducers Tubular formation Tyrosine angiogenin base career glomerulosclerosis human PTPN6 protein in vivo inorganic phosphate kidney vascular structure member prevent receptor tyrphostin AG-490 vascular endothelial dysfunction

项目摘要

DESCRIPTION (provided by applicant): My career goal is to have an independent academic research laboratory that explores the vascular and renal intracellular signaling events which are involved in the development of complications from hypertension and diabetes. The treatment of these diseases and their complications presents a large financial burden on the health care system and a loss in the quality of life for millions of patients. Understanding the molecular basis of the progression of these diseases and complications will provide new treatment options. One signaling pathway which in vitro data suggests may be involved in the adverse consequences of these diseases is the JAK/STAT pathway. We have also recently demonstrated in vivo that activation of the JAK/STAT pathway is involved in the development of protenuria in type I diabetes. However, there are currently no data investigating this pathway and its mechanisms of regulation in hypertension. Therefore, we propose to test the hypothesis that activation of the JAK/STAT pathway in vivo during hypertension contributes to the development of vascular endothelial dysfunction and renal complications as assessed by alterations in glomerular filtrate rate (GFR), renal blood flow and the development of glomerular sclerosis. The goal of these proposed studies is to use an integrative approach combining whole animal physiology with a biochemical analysis of the intracellular signaling mechanisms to elucidate the molecular mechanisms involved in the development of complications. To achieve this goal we are proposing four specific aims. Specific Aim 1: Determine if activation of the JAK2/STAT pathway contributes to the development of hypertension via a vascular or renal tubular effect. Specific Aim 2: Determine whether activation of the JAK/STAT pathway occurs in multiple models of hypertension. Specific Aim 3: Determine the effects of hypertension on the role of the cytosolic protein tyrosine phosphates, SHP-1, SHP-2 and PTP-1B, and suppressors of cytokine signaling (SOCS) that regulate the JAK/STAT pathway. Specific Aim 4: Determine the interaction of the JAK/STAT with other signaling pathways already implicated in hypertension, specifically PKC, PKA, Rho-kinase and PI3-kinase. Understanding the molecular changes that contribute to the development of end-organ damage in disease states is critical to create additional clinical interventions that could be used in conjunction with traditional therapy.

描述(由申请人提供)：我的职业目标是拥有一个独立的学术研究实验室，探索与高血压和糖尿病并发症的发生有关的血管和肾脏细胞内信号事件。这些疾病及其并发症的治疗给保健系统带来了巨大的财政负担，并使数百万患者丧失了生活质量。了解这些疾病和并发症进展的分子基础将提供新的治疗选择。体外数据表明，JAK/STAT通路可能参与了这些疾病的不良后果。我们最近还在体内证明了JAK/STAT通路的激活与I型糖尿病蛋白尿的发生有关。然而，目前还没有研究这一途径及其在高血压中的调节机制的数据。因此，我们建议通过肾小球滤过率(GFR)、肾血流量和肾小球硬化的发展来评估高血压期间体内JAK/STAT通路的激活有助于血管内皮功能障碍和肾脏并发症的发展的假说。这些研究的目的是使用一种综合的方法，结合整体动物生理学和细胞内信号机制的生化分析来阐明参与并发症发生的分子机制。为了实现这一目标，我们提出了四个具体目标。具体目标1：确定JAK2/STAT通路的激活是否通过血管或肾小管效应促进高血压的发展。具体目标2：确定JAK/STAT通路的激活是否在多种高血压模型中发生。具体目标3：确定高血压对胞浆蛋白酪氨酸磷酸酯、SHP-1、SHP-2和PTP-1B以及调节JAK/STAT通路的细胞因子信号(SOCs)的作用的影响。具体目标4：确定JAK/STAT与其他与高血压有关的信号通路的相互作用，特别是PKC、PKA、Rho-Kinase和PI3-Kinase。了解在疾病状态下导致终末器官损害发展的分子变化对于创建可与传统疗法结合使用的额外临床干预措施至关重要。