BMP and FGF Signaling in kidney progenitor cells

描述（由申请人提供）：我们实验室研究的长期目标是开发技术来替代因肾单位损失而导致不可逆肾脏损伤的儿童和成人的肾组织。目前，不可逆的肾脏损伤导致透析和移植，这种情况会带来相当大的发病率和死亡率，每年给医疗保健系统造成的损失远远超过 100 亿美元。由于肾单位由至少 15 种不同的细胞类型组成，排列成高度专业化的结构，因此生成新肾单位的最可行方法是能够操纵肾干祖细胞，类似于胚胎肾中发现的细胞，这些细胞经过基因编程形成完整的肾单位。开发基于干细胞的不可逆肾病再生疗法必须实现两个关键方面。首先，有必要加深我们对肾干细胞和祖细胞群如何维持以及肾单位如何分化的了解。这是本次赠款的主题。此外，有必要开发将胚胎干细胞和诱导多能干（IPS）细胞转化为肾祖细胞的方法。总之，实现这些目标将使我们更接近一个时代，让患有肾病的人能够利用干细胞研究的最新重大进展。在这笔资助中，我们提出了新的研究，重点关注骨形态发生蛋白 (BMP) 和成纤维细胞生长因子 (FGF) 在调节肾干细胞和祖细胞中的作用。我们重点关注输尿管芽、肾小管前聚集体和祖细胞本身表达的 BMP 和 FGF 信号可以调节发育中肾单位中祖细胞群的新途径。我们假设发育中的肾脏中这些生长因子家族之间存在重要的相互作用，类似于在其他发育系统中观察到的情况。 公共健康相关性：这项资助研究了肾脏发育一组干细胞以形成成熟肾脏的机制。我们的长期目标是利用这些细胞进行最终的再生疗法，以治疗肾脏受到不可逆损伤的儿童和成人的肾脏疾病，这些人患有慢性肾功能衰竭，否则需要透析或移植。

DESCRIPTION (provided by applicant): The long-term goal of our laboratory's research is to develop technologies to replace kidney tissue in children and adults with irreversible kidney damage, resulting from the loss of nephrons. At present, irreversible kidney damage leads to dialysis and transplantation, situations that carry with them considerable morbidity and mortality and cost the health care system well over 10 billion dollars annually. As nephrons are composed of at least 15 distinct cell types, arranged into a highly specialized architecture, the most feasible approach to generating new nephrons is to be able to manipulate kidney stem-progenitor cells, similar to those found in the embryonic kidney, that are genetically programmed to form whole nephrons. There are two crucial aspects that must both be achieved to develop stem cell- based regenerative therapies for irreversible kidney disease. First, it will be necessary to increase our understanding of how kidney stem and progenitor cell populations are maintained and how nephrons differentiate. This is the subject of the present grant. Additionally, it will be necessary to develop approaches to transform embryonic stem cells and induced pluripotent stem (IPS) cells into kidney progenitor cells. Together, achieving these goals will move us closer to a time where individuals suffering from kidney disease will be able to take advantage of the recent great advancements in stem cell research. In this grant, we propose new studies that center on the role of Bone Morphogenetic Proteins (BMPs) and Fibroblast Growth Factors (FGFs) to regulate kidney stem and progenitor cells. We focus on novel pathways through which BMP and FGF signals expressed by the ureteric bud, pretubular aggregate and progenitor cells themselves can regulate progenitor cell populations in the developing nephron. We hypothesize that there are important interactions between these families of growth factors in the developing kidney, similar to what is observed in other developmental systems. PUBLIC HEALTH RELEVANCE: This grant examines the mechanisms by which kidneys develops a set of stem cells that give rise to the mature kidney. Our long-range goal is to harness these cells for eventual regenerative therapies to treat kidney disease in children and adults with irreversible damage to their kidneys, who have chronic renal failure that would otherwise require dialysis or transplantation.