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

摘要 我们将研究丝氨酸苏氨酸激酶分割缺陷(PAR)1a和1b在 肾小管损伤后的适应性和非适应性修复。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的激活：这在 第一次在Par1和Notch信令之间建立链路。我们假设：Par1a/b激酶是 肾损伤对增殖的祖细胞的激活及其对Jag1-Notch依赖性的调节 和独立的促纤维化途径。使用可诱导的细胞特异性缺失P1a/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 将研究新的Par1-Notch链接的机制。我们的具体目标是：1) 显示Par1a/b通过Notch途径调节对肾小管损伤的反应； 证明肾小管祖细胞中的Par1a/b促进适应不良修复。

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.