Kidney Progenitor Cells in Disease

描述（由申请人提供）：了解损伤后肾脏再生的正常机制对于开发新疗法以应对慢性肾脏疾病和器官衰竭日益增加的负担至关重要。 虽然成年哺乳动物的肾脏缺乏能够再生整个肾单位的肾单位祖细胞，但它具有显著的再生能力。最近的研究主要集中在肾小管再生，但未能确定在成人肾脏上皮祖细胞。然而，很少有人关注脉管系统。这个项目的总体目标是 本申请的目的是鉴定和研究成人肾静止干/祖细胞。因此，一个由四名专家组成的团队汇集了独特的背景和技能，包括干细胞生物学。肾素细胞生物学、肾脏发育、肾小球和间质损伤以及再生医学专门鉴定和表征肾脏内的潜在祖细胞。 在使用独特的遗传工具进行的令人兴奋的新的可行性研究中，这些研究人员通过鉴定在肾损伤和生长反应中被激活的假定的潜在祖细胞，显示了最近合作的证据。这些细胞产生的后代重新填充肾小球（足细胞）和肾小球（周细胞和内皮细胞）的血管壁细胞。 在R24应用的第一年（第一阶段，在这里讨论），研究人员计划 在肾脏中使用两种不同但互补的最先进的命运定位技术来无可辩驳地确定这些潜伏祖细胞的存在和能力。假设第一阶段取得成功，研究人员将提出第二阶段（R24应用的第2-5年），他们将系统地剖析这些祖细胞是如何被激活的， 存在于这些祖细胞的后代中，研究它们在衰老中的能力，并试图利用这些祖细胞来促进肾细胞再生。 公共卫生相关性：急性肾损伤、慢性肾病和终末期肾病是主要的健康负担。 了解肾脏如何响应损伤而再生，对于产生预防或限制慢性肾脏疾病或终末期肾脏疾病发展的新疗法至关重要。这些初步研究将研究成人肾脏中的祖细胞，这些祖细胞具有生成新肾细胞的能力，特别是肾脏血管的细胞。研究人员将确定这些祖细胞在肾损伤后再生中的重要性。

DESCRIPTION (provided by applicant): Understanding normal mechanisms of kidney regeneration in response to injuries is of vital importance to developing new therapies to tackle the increasing burden of chronic kidney disease and organ failure. Although the adult mammalian kidney lacks nephron progenitors that could regenerate entire nephrons, nevertheless it has remarkable capacity to regenerate. Recent studies have focused predominantly on tubule regeneration, yet have failed to identify an epithelial progenitor cell in adult kidney. However, there has been little attention to the vasculature. The overall goal of this application is to identify and study adult kidney quiescent stem/progenitor cells. Accordingly, a team of four experts has come together bringing unique backgrounds and skills including stem cell biology. Renin cell biology, kidney development, glomerular and interstitial injuries, and Regenerative Medicine specifically identify and characterize latent progenitors lying within the kidney. In exciting new feasibility studies using unique genetic tools, these investigators have shown evidence of recent collaborations by identifying putative latent progenitor cells that are activated in response to kidney injuries and growth. These cells yield progeny that repopulate vascular mural cells of the glomerulus (podocytes) and interstitium (pericytes and endothelial cells). In the first year of this R24 application (Phase I, addressed here) the investigators plan to establish irrefutably the presence and capacity of these latent progenitors using two distinct but complementary state-of-the-art fate mapping techniques in kidneys. Assuming the success of Phase I, the Investigators will then propose Phase II (years 2-5 of the R24 application) in which they will methodically dissect how these progenitors are activated, what lineal restrictions exist in the progeny of these progenitors, study their capacity in aging, and attempt to harness these progenitors to promote kidney cell regeneration. PUBLIC HEALTH RELEVANCE: Acute Kidney Injury, Chronic Kidney Disease and End Stage Kidney Disease are major health burdens. Understanding how the kidney regenerates in response to injuries is vital to generating new therapies that will prevent or limit the developmen of chronic kidney disease or end stage kidney disease. These initial studies will study progenitor cells in the adult kidney that have the capacity to generate new kidney cells, particularly of the blood vessels of the kidney. The investigators will determine how important these progenitors are in regeneration after kidney damage.