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丢失而导致不可逆性肾损伤的儿童和成人的肾脏组织。目前，不可逆转的肾脏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，每年花费医疗保健系统远远超过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架构，因此产生新肾单位最可行的方法是能够操纵肾脏干细胞--类似于在胚胎肾脏中发现的干细胞，这些干细胞通过基因编程形成完整的肾单位。要开发基于干细胞的不可逆肾脏疾病的再生疗法，必须同时实现两个关键方面。首先，有必要增加我们对肾脏干细胞和祖细胞群体如何维持以及肾单位如何分化的理解。这就是目前拨款的主题。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。总而言之，实现这些目标将使我们更接近肾脏疾病患者能够利用最近干细胞研究的巨大进步的时代。在这项拨款中，我们建议进行新的研究，重点是骨形态发生蛋白(BMPs)和成纤维细胞生长因子(FGFs)在调节肾脏干细胞和祖细胞方面的作用。我们关注的是由输尿管芽、肾小管前集合体和祖细胞本身表达的BMP和成纤维细胞生长因子信号如何调节发育中的肾单位的祖细胞数量。我们假设，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。 与公共健康相关：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治疗，以治疗肾脏受到不可逆转损害的儿童和成人的肾脏疾病，这些儿童和成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.