Cell specific Partitioning Defective Par1a/b deletion effects on renal repair

细胞特异性分区缺陷 Par1a/b 缺失对肾修复的影响

• 批准号: 10346205
• 负责人: Kimberly Jean Reidy
• 金额: $ 41.45万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10346205
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Adult; Cell Cycle; Cell Differentiation process; Cells; Chronic; Chronic Kidney Failure; Clinical; Data; Development; Dialysis procedure; Disease Progression; Epithelial; Epithelial Cells; Family; Fibrosis; Folic Acid; Gene Expression; Goals; Human; Impairment; Infiltration; Inflammatory; Injections; Injury; Injury to Kidney; Kidney; Kidney Diseases; Knowledge; Laboratories; Link; Membrane; Modeling; Mus; Myofibroblast; Notch Signaling Pathway; Pathway interactions; Persons; Pharmacology; Phosphotransferases; Population; Proliferating; Protein Family; Protein-Serine-Threonine Kinases; Recovery; Regulation; Renal function; Renal tubule structure; Reperfusion Injury; Role; Signal Pathway; Signal Transduction; Testing; Tetanus Helper Peptide; Time; Tubular formation; Up-Regulation; Ureteral obstruction; WNT Signaling Pathway; epithelial stem cell; human disease; in vivo; inhibitor; innovation; insight; interstitial; kidney fibrosis; kidney repair; knock-down; loss of function; member; mouse model; new therapeutic target; notch protein; novel; prevent; repaired; response; single-cell RNA sequencing; stem cells; synergism; targeted treatment; therapeutic target; tool

Abstract We will study the role of serine threonine kinases Partitioning defective (Par) 1a and 1b in adaptive and maladaptive repair following tubular injury. In studies by our laboratory of the developing kidney, dual loss of Par1a and 1b impaired Notch activation: this demonstrated for the first time a link between Par1 and Notch signaling. We hypothesize: Par1a/b kinases are activated in proliferating progenitor cells by kidney injury and regulate Jag1-Notch dependent and independent pro-fibrotic pathways. Using inducible cell specific deletion of both Par1a/b in mice, we will test effect of Par1a/b on Notch activation and progenitor cells following injury. We will investigate the mechanisms underlying the novel Par1-Notch link. Our specific aims are: 1) Show that Par1a/b regulates the response to kidney tubule injury via the Notch pathway; and 2) Demonstrate that Par1a/b in tubular progenitor cells promotes maladaptive repair.

抽象的 我们将研究丝氨酸苏氨酸激酶分配缺陷 (Par) 1a 和 1b 在 肾小管损伤后的适应性和适应不良修复。在我们实验室的研究中 发育中的肾脏，Par1a 和 1b 的双重缺失损害了 Notch 激活：这证明了 第一次在 Par1 和 Notch 信令之间建立联系。我们假设：Par1a/b 激酶是 通过肾损伤在增殖祖细胞中激活并调节 Jag1-Notch 依赖性 和独立的促纤维化途径。使用诱导细胞特异性删除 Par1a/b 小鼠，我们将测试 Par1a/b 对损伤后 Notch 激活和祖细胞的影响。我们 将研究新颖的 Par1-Notch 链接的潜在机制。我们的具体目标是：1） 表明Par1a/b通过Notch通路调节对肾小管损伤的反应；和 2) 证明肾小管祖细胞中的 Par1a/b 促进适应不良修复。