ROLE OF NOTCH AND KIDNEY DEVELOPMENT

NOTCH 和肾脏发育的作用

基本信息

批准号：
8254453
负责人：
RAPHAEL KOPAN
金额：
$ 40.34万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2013-08-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8254453
关键词：
Accounting Acute Address Adhesions Adopted Adult Affect Age Alagille Syndrome Animals Biology Cell Communication Cell Culture Techniques Cell Differentiation process Cell Lineage Cells Child Chronic Kidney Failure Clinic Clinical Cyst Cystic kidney Development Distal Dose Epithelial Epithelial Cells Epithelium Evaluation Frequencies Functional disorder Funding Gatekeeping Generations Genes Genetic Goals Government Grant Head Health Homeostasis Human Injury Intervention Kidney Kidney Diseases Knockout Mice Life Logic Maintenance Maps Mediating Modeling Molecular Mus Mutation Natural regeneration Nephrons Organ Culture Techniques Papillary Papillary adenoma Patients Persons Physiological Play Population Process Proximal Kidney Tubules Renal Adenoma Renal Cell Carcinoma Renal carcinoma Renal tubule structure Research Role Secure Shapes Signal Transduction Specific qualifier value Staging Stenosis Stimulus Stratification Structure System Testing Therapeutic Time Tubular formation Vesicle adenoma ciliopathy clinically relevant embryonic stem cell experience genetic analysis improved in vitro Model injured loss of function nephrogenesis neuronal cell body notch protein podocyte progenitor receptor renal epithelium therapy design tool translational approach

项目摘要

Genetic analysis conducted during the previous funding period defined two stages where Notch signals play an important role in kidney biology. The first essential function of Notch is during nephron segmentation. Notch2 signals block distal identities and promote proximal tubule (PT) and podocyte (POD) identities either cell autonomously or inducing them in neighboring cells. This activity is required only transiently, becoming dispensable after S-shaped body (SB) formation. A second important function of Notch signals is to act as gatekeepers of renal tubular epithelial homeostasis during adulthood; in their absence, cysts and renal dysfunction develop spontaneously in a substantial fraction of outbred animals with some cysts containing cells that continue to divide and develop papillary adenomas, thought to be the precursor for papillary renal cell carcinoma (PRCC). Injury increases the frequency of cyst and papillary adenoma formation. While these findings explain why reduced Notch2 signaling in humans causes Alagille syndromes (AGS), and suggest that elevating Notch1 activity in such patients should improve health, they do not establish if/how Notch signals direct the acquisition of PT and POD fates. We will take advantage of cell lineage tracing tools prepared during the previous funding period to address the issue of whether the cellular organization in the SB, at the time of Notch2 activation, underlies the organization of nephron sub-structures in the adult nephron and map the potential of de-differentiated renal PT recovering from injury in the adult. These fate mapping studies will allow us to ask if SB cells experiencing Notch activity are fated to become PT, POD, neither, or both, and if de-differentiated adult renal epithelial cells are fate-restricted or oligopotential. The results will direct our subsequent search for genes capable of enhancing POD and PT regeneration in injured adults. In Aim 2, we will ask how these cells acquire their fates. In Aim 3, we will determine the mechanistic contribution of Notch loss to cyst and adenoma formation in adults. In Aim 4, we will develop strategies to transiently augment Notch1 activity in AGS and PRCC with the translational goal of developing clinical interventions aimed at compensating for Notch signal reduction reduction in AGS.

上一资助期间进行的基因分析定义了 Notch 信号发挥作用的两个阶段在肾脏生物学中发挥重要作用。 Notch 的第一个基本功能是在肾单位分割过程中。 Notch2 信号阻断远端身份并促进近端小管 (PT) 和足细胞 (POD) 身份细胞自主地或在邻近细胞中诱导它们。此活动仅是暂时需要的，成为 S形体（SB）形成后可有可无。 Notch 信号的第二个重要功能是充当成年期肾小管上皮稳态的看门人；如果没有它们，囊肿和肾大部分远交动物的功能障碍会自发发生，其中一些包囊含有继续分裂和发育乳头状腺瘤的细胞，被认为是乳头状肾的前身细胞癌（PRCC）。损伤会增加囊肿和乳头状腺瘤形成的频率。虽然这些研究结果解释了为什么人类中 Notch2 信号传导减少会导致 Alagille 综合征 (AGS)，并表明认为提高此类患者的 Notch1 活性可以改善健康，但他们没有确定 Notch1 是否/如何信号指导 PT 和 POD 命运的获取。我们将利用细胞谱系追踪工具在上一个供资期间准备解决细胞组织是否在 SB 在 Notch2 激活时是成人肾单位亚结构组织的基础肾单位并绘制成人去分化肾 PT 从损伤中恢复的潜力。这些命运绘图研究将使我们能够询问经历 Notch 活性的 SB 细胞是否注定会成为 PT、POD、两者都不是，或者两者都有，并且如果去分化的成年肾上皮细胞是命运限制性的或寡能的。这结果将指导我们后续寻找能够增强损伤后 POD 和 PT 再生的基因成年人。在目标 2 中，我们将询问这些细胞如何获得它们的命运。在目标 3 中，我们将确定机制 Notch 缺失对成人囊肿和腺瘤形成的贡献。在目标 4 中，我们将制定战略暂时增强 AGS 和 PRCC 中的 Notch1 活性，以实现临床开发的转化目标旨在补偿 AGS 中 Notch 信号减少的干预措施。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development.

DOI：
10.1016/j.devcel.2010.04.008
发表时间：
2010-05-18
期刊：
DEVELOPMENTAL CELL
影响因子：
11.8
作者：
Costantini, Frank;Kopan, Raphael
通讯作者：
Kopan, Raphael

Notch: architect, landscaper, and guardian of the intestine.

DOI：
10.1053/j.gastro.2011.06.003
发表时间：
2011-08
期刊：
Gastroenterology
影响因子：
29.4
作者：
Vooijs M;Liu Z;Kopan R
通讯作者：
Kopan R

Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells.

DOI：
10.1053/j.gastro.2011.01.005
发表时间：
2011-04
期刊：
Gastroenterology
影响因子：
29.4
作者：
Pellegrinet L;Rodilla V;Liu Z;Chen S;Koch U;Espinosa L;Kaestner KH;Kopan R;Lewis J;Radtke F
通讯作者：
Radtke F

Organ culture and immunostaining of mouse embryonic kidneys.