BMP and FGF Signaling in kidney progenitor cells

描述（由申请人提供）：我们实验室的长期研究目标是开发替代儿童和成人肾组织的技术，这些肾脏组织因肾单位的丧失而遭受不可逆的肾损伤。目前，不可逆转的肾损伤导致透析和移植，这种情况伴随着相当高的发病率和死亡率，每年花费医疗保健系统超过100亿美元。由于肾单位由至少15种不同的细胞类型组成，排列成一个高度专业化的结构，产生新肾单位的最可行方法是能够操纵肾干细胞祖细胞，类似于胚胎肾脏中的那些细胞，它们被基因编程形成完整的肾单位。有两个至关重要的方面，必须同时实现发展干细胞再生治疗不可逆的肾脏疾病。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。这就是本次拨款的主题。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这样一个时代：患有肾脏疾病的人将能够利用干细胞研究的最新巨大进展。在这项资助中，我们提出了关于骨形态发生蛋白（BMPs）和成纤维细胞生长因子（FGFs）在调节肾干细胞和祖细胞中的作用的新研究。我们关注输尿管芽、小管前聚集体和祖细胞自身表达的BMP和FGF信号调节发育中的肾元祖细胞群的新途径。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情况。

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.