Role of COX2 in Medullary Interstitial Cell Survival and Function

COX2 在髓质间质细胞存活和功能中的作用

• 批准号: 7728127
• 负责人: GILBERT WOLFRAM MOECKEL
• 金额: $ 5.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728127
• 关键词: Address; Apoptosis; Apoptotic; Blood Pressure; Blood flow; Cell Death; Cell Survival; Cell physiology; Cells; Condition; Coxibs; Data; Dominant-Negative Mutation; Duct (organ) structure; E protein; Edema; Eicosanoids; Excretory function; FYN gene; Goals; Health; High Blood Pressure; Hypertension; Hypotension; Impairment; In Vitro; Induction of Apoptosis; Injury; Kidney; Lead; Limb structure; MAP Kinase Gene; Maintenance; Mediating; Membrane Potentials; Mitochondria; Morbidity - disease rate; Myocardial Infarction; Null Lymphocytes; PTGS2 gene; Pharmaceutical Preparations; Process; Production; Prostaglandins; Prostaglandins E; Protein Overexpression; Public Health; Regulation; Role; Signal Pathway; Signal Transduction; Site; Societies; Stress; Stroke; Testing; Therapeutic; Thick; Time; Vasopressins; absorption; base; blood pressure regulation; cyclooxygenase 2; design; in vivo; insight; interstitial cell; kidney cell; kidney medulla; mitochondrial membrane; mortality; paracrine; prevent; prostaglandin EP3 receptor; src-Family Kinases

DESCRIPTION (provided by applicant): Hypertension is an important public health problem and one of the major causes of morbidity and mortality in all western societies. Several studies have emphasized the importance of the renal medullary blood flow in long term regulation of blood pressure. Medullary blood flow is regulated by eicosanoids such as prostaglandins, which are produced in the medulla and act locally. The medullary interstitial cell (MIC) is the predominant site of medullary prostanoid production. Prostanoid-dependent cell survival mechanisms, such as organic osmolyte accumulation, protect cells in the renal medulla against hyperosmotic stress. We hypothesize that impairment of prostanoid-dependent MIC survival leads to decrease in medullary blood flow and rise in arterial blood pressure. Our hypothesis is based on our exciting in vivo and in vitro data that show that inhibition of renal prostaglandin synthesis leads to both impairment of medullary interstitial cell survival and medullary blood flow. However, the exact mechanisms how prostanoids mediate osmolyte accumulation and how these ameliorate hypertonic stress-induced injury to medullary interstitial cells is unknown. We will test our hypothesis by examining the mechanisms that lead to hypertonicity-induced cell death, and how osmolyte prevent mitochondrial injury under hyperosmotic conditions, (specific aim 1). We will then progress to investigate the role of Src family kinases (SFKs) on hypertonicity-induced signaling that mediates increased prostanoid synthesis (COX2) and osmolyte accumulation (TonEBP/NFAT5) (specific aim 2). Finally, we will examine the role of the prostaglandin E protein receptor (EP3), which is highly prevalent in the medulla, on osmolyte transport regulation and cell survival in vivo and in vitro (specific aim 3). The mechanisms that regulate medullary blood flow and the role of the medullary interstitial cell in long term blood pressure regulation are poorly understood. The studies in this proposal address this major gap in our understanding. Our long term goals are to gain insight into the mechanistic process that leads to the important health problem of hypertension. It is necessary to understand these processes in order to design effective therapeutic approaches and develop new drugs to treat hypertension. High blood pressure is a common health problem and a major cause of heart attack and stroke in western societies. Several studies have shown the importance of good blood flow to the kidney for the maintenance of low blood pressure. Certain kidney cells are super-regulators of blood flow and their survival is highly important to keep blood pressure low. The goals of this study are to understand better how these super-regulator cells survive and keep blood pressure low. It is necessary to understand how these cells function in order to design better drugs to treat high blood pressure.

描述（由申请人提供）： 高血压是一个重要的公共卫生问题，也是所有西方社会发病和死亡率的主要原因之一。几项研究强调了肾脏髓质血流在长期调节血压中的重要性。髓样血流受诸如前列腺素等类类烷的调节，这些素是在髓质中产生的，并在局部起作用。髓质间质细胞（MIC）是髓样产生的主要部位。前列腺素依赖性细胞存活机制，例如有机渗透液积累，可保护肾脏髓质中的细胞免受高渗性胁迫。我们假设前列腺素依赖性MIC存活的损害会导致髓质血流的降低和动脉血压的升高。我们的假设基于我们令人兴奋的体内和体外数据，这些数据表明抑制肾脏前列腺素合成会导致髓质间质细胞存活和髓样血流的损害。然而，确切的机制如何介导渗透液积累，以及这些如何改善高血压胁迫诱导的髓质间质细胞损伤是未知的。我们将通过检查导致高渗性诱导细胞死亡的机制来检验我们的假设，以及在高渗条件下如何预防线粒体损伤（特定目标1）。然后，我们将进步以研究SRC家族激酶（SFK）对高渗性诱导的信号传导的作用，从而介导增加的前类动物合成（COX2）和Osmolyte累积（ToneBP/NFAT5）（特定目标2）。最后，我们将研究前列腺素E蛋白受体（EP3）的作用，该蛋白质受体在髓质中非常普遍，在体内和体外（特定的目标3）中，在髓质转运调控和细胞存活中的作用（特定目标3）。对长期血压调节中调节髓质血流和髓质间质细胞的作用的机制众所周知。该提案中的研究解决了我们理解的这一主要差距。我们的长期目标是深入了解导致重要健康问题的机械过程。有必要理解这些过程，以设计有效的治疗方法并开发新药来治疗高血压。高血压是一个常见的健康问题，也是西方社会心脏病发作和中风的主要原因。几项研究表明，良好的血液流向肾脏的重要性对于维持低血压的维持。某些肾细胞是血流的超级调节剂，其存活对于保持血压低非常重要。这项研究的目标是更好地了解这些超调节剂细胞如何生存并保持血压较低。有必要了解这些细胞如何发挥作用，以设计更好的药物来治疗高血压。