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：
8116640
负责人：
Amy Banes-Berceli
金额：
$ 24.05万
依托单位：
OAKLAND UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-10 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8116640
关键词：
Adult Affect American 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 Dose Extracellular Matrix Proteins Glomerular Mesangial Cell Goals Growth Hypertension In Vitro Inositol Instruction Intervention JAK2 gene Kidney Kidney Diseases L-Type Calcium Channels MAP Kinase Gene Mediating Modeling Molecular Muscle Contraction Norepinephrine Organ PTPN1 gene PTPN11 gene PTPN6 gene Pathologic Processes Pathway interactions Phosphotransferases Physiological Physiology Play Protein Kinase C Protein Tyrosine Phosphatase Renal Blood Flow Rho-associated kinase Role Signal Pathway Signal Transduction Smooth Muscle Myocytes Sodium Chloride Testing Vasoconstrictor Agents adverse outcome glomerulosclerosis in vivo inhibitor/antagonist kidney vascular structure member traditional therapy vascular endothelial dysfunction

项目摘要

PROJECT SUMMARY (See instructions): One signaling pathway which data suggests may be involved in the adverse consequences of diabetes and hypertension is the JAK/STAT pathway. Our data support the idea that activation of this pathway is critical to the ability of ANGII to cause h3T)ertension in the models of ANG Il-high salt and high dose ANG II (normal salt). Preliminary data further suggest JAK2 appears to play a critical role in the molecular mechanisms utilized by ANG II to cause vascular contraction. These studies suggest that an alteration in the inhibitor of JAK2 activity, SHP-1, may be involved in the activation of JAK2 observed. Furthermore, in vivo, Norepinephrine also activates JAK2 during hypertension suggesting that JAK2 may be a common agent for the increase in blood pressure. 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 three specific aims. Specific Aim 1: Determine if the same members of the JAK/STAT pathway are activated in the DOCA-salt, ANG Il-high salt and NE-lnfiised models of hypertension. Specific Aim 2: Determine the effects of hypertension on the role of the cytosolic protein tyrosine phosphatases, SHP-1, SHP-2 and PTP-IB, and suppressors of c3rtokine signaling (SOCS) that regulate the JAK/STAT pathway. Specific Aim 3: 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 wnth traditional therapy.

项目摘要（参见说明）：数据表明，一种信号通路可能与糖尿病和糖尿病的不良后果有关高血压是JAK/STAT通路。我们的数据支持这一观点，即激活该途径对于 ANGII在ANG II-高盐和高剂量ANG II(正常盐)模型中引起高血压的能力。初步数据进一步表明 JAK2 似乎在利用的分子机制中发挥着关键作用 ANG II引起血管收缩。这些研究表明 JAK2 活性抑制剂的改变，观察到SHP-1可能参与JAK2的激活。此外，在体内，去甲肾上腺素还可以激活高血压期间的 JAK2 表明 JAK2 可能是血压升高的常见因素。因此，我们建议检验以下假设：体内 JAK/STAT 通路的激活高血压会导致血管内皮功能障碍和肾脏并发症的发生通过肾小球滤过率 (GFR)、肾血流量和肾小球发育的变化进行评估硬化。这些拟议研究的目标是使用一种将整个动物结合起来的综合方法生理学，对细胞内信号传导机制进行生化分析，以阐明分子机制涉及并发症发生的机制。为实现这一目标，我们提出三项具体建议目标。具体目标 1：确定 JAK/STAT 通路的相同成员是否在 DOCA-盐中被激活， ANG II-高盐和NE-高血压模型。具体目标 2：确定高血压对胞浆蛋白酪氨酸磷酸酶、SHP-1、SHP-2 和 PTP-IB 以及 c3rtokine 抑制剂的作用调节 JAK/STAT 通路的信号传导 (SOCS)。具体目标 3：确定 JAK/STAT 的相互作用与高血压相关的其他信号通路，特别是 PKC、PKA、Rho 激酶和 PI3- 激酶。了解导致终末器官损伤发生的分子变化疾病状态对于制定额外的临床干预措施至关重要，这些干预措施可以与疾病状态结合使用传统疗法。