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

• 批准号: 7928767
• 负责人: Amy Banes-Berceli
• 金额: $ 24.29万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7928767
• 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; 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; Renal Blood Flow; Rho-associated kinase; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Sodium Chloride; Testing; Vasoconstrictor Agents; adverse outcome; glomerulosclerosis; human PTPN6 protein; in vivo; inhibitor/antagonist; kidney vascular structure; member; traditional therapy; vascular endothelial dysfunction

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（请参阅说明）： 数据表明可能涉及糖尿病和 高血压是JAK/STAT途径。我们的数据支持以下想法，即该途径的激活对 ANGII在Ang Il-High盐和高剂量ANG II（正常盐）模型中引起H3T）的能力。 进一步的数据进一步表明JAK2似乎在分子机制中起着至关重要的作用 ANG II引起血管收缩。这些研究表明，JAK2活性抑制剂的改变， SHP-1可能与观察到的JAK2激活有关。此外，在体内，去甲肾上腺素也激活 高血压期间的JAK2表明JAK2可能是血压升高的常见药物。 因此，我们建议检验以下假设。 高血压有助于血管内皮功能障碍和肾脏并发症的发展 通过肾小球滤液速率（GFR）的改变，肾血流和肾小球发展评估 硬化。这些建议的研究的目的是使用将整个动物结合在一起的综合方法 生理学，对细胞内信号传导机制进行生化分析，以阐明分子 并发症发展涉及的机制。为了实现这一目标，我们提出了三个特定的 目标。特定目标1：确定在DOCA-SALT中激活JAK/STAT途径的相同成员， Ang Il-Hir-High盐和高血压的NE-LNFINFINED模型。特定目标2：确定高血压对 胞质蛋白酪氨酸磷酸酶，SHP-1，SHP-2和PTP-IB以及C3RTOKINE的抑制剂的作用 信号（SOC）调节JAK/STAT途径。特定目标3：确定jak/stat的相互作用 与已经与高血压有关的其他信号通路，特别是PKC，PKA，Rho-kinase和Pi3-- 激酶。了解有助于发展最终器官损伤的分子变化 疾病状态对于创建可以在wnth结合使用的其他临床干预措施至关重要 传统疗法。