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，以替代因肾单位丢失而造成不可逆肾损伤的儿童和成人的肾组织。目前，不可逆转的肾损伤导致透析和移植，这些情况伴随着相当大的发病率和死亡率，并且每年花费卫生保健系统超过100亿美元。由于肾单位由至少15种不同的细胞类型组成，排列成高度特化的结构，产生新肾单位的最可行的方法是能够操纵肾干祖细胞，类似于胚胎肾中发现的那些，其被遗传编程以形成整个肾单位。有两个关键的方面，必须同时实现开发干细胞为基础的再生疗法不可逆转的肾脏疾病。首先，有必要增加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理解。这是目前赠款的主题。此外，有必要开发将胚胎干细胞和诱导多能干细胞（IPS）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患有肾脏疾病的人能够利用干细胞研究最近取得的巨大进展的时代。在这项资助中，我们提出了新的研究，集中在骨形态发生蛋白（BMP）和成纤维细胞生长因子（FGF）的作用，以调节肾脏干细胞和祖细胞。我们专注于新的途径，通过该途径，由输尿管芽，pretubular聚集体和祖细胞本身表达的BMP和FGF信号可以调节祖细胞群在发育中的肾单位。我们推测，在发育中的肾脏中，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。 公共卫生相关性：该基金会研究肾脏发育成一组干细胞的机制，这些干细胞会产生成熟的肾脏。我们的长期目标是利用这些细胞进行最终的再生治疗，以治疗肾脏不可逆损伤的儿童和成人肾脏疾病，这些人患有慢性肾衰竭，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.