BMP and FGF Signaling in kidney progenitor cells

肾祖细胞中的 BMP 和 FGF 信号转导

基本信息

批准号：
8494042
负责人：
Jordan A Kreidberg
金额：
$ 33.6万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

项目摘要

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.

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，以替代因肾脏丧失而导致的肾脏损伤的儿童和成人的肾脏组织。目前，不可逆转的肾脏损害导致透析和移植，伴随着大量发病率和死亡率的情况以及每年超过100亿美元的医疗保健系统造成的。由于肾接由至少15种不同的细胞类型组成，分为高度专业的结构，因此产生新肾脏的最可行方法是能够操纵肾脏干性细胞，类似于在胚胎肾脏中发现的，这些细胞被遗传编程以形成整个肾小球。为了开发基于干细胞的不可逆肾脏疾病的基于干细胞的再生疗法，必须实现两个关键方面。首先，有必要提高我们对肾脏茎和祖细胞细胞群体如何保持以及肾单位分化的理解。这是当前赠款的主题。此外，有必要开发方法将胚胎干细胞和诱导多能干（IPS）细胞转化为肾脏祖细胞。共同实现这些目标将使我们更加接近患有肾脏疾病的人将能够利用最近的干细胞研究进步。在这笔赠款中，我们提出了新的研究，该研究以骨形态发生蛋白（BMP）和成纤维细胞生长因子（FGF）的作用为中心，以调节肾脏茎和祖细胞。我们专注于新的途径，BMP和FGF信号由输尿管芽表达，序列骨料和祖细胞本身可以调节发育中的肾单位中的祖细胞群体。我们假设这些发展肾脏中这些生长因子家族之间存在重要的相互作用，类似于其他发育系统中观察到的肾脏。公共卫生相关性：这项拨款研究了肾脏开发出一组干细胞的机制，这些干细胞引起了成熟的肾脏。我们的远距离目标是利用这些细胞的最终再生疗法，以治疗对肾脏造成不可逆转损害的儿童和成人的肾脏疾病，肾脏具有慢性肾衰竭，否则需要透析或移植。