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.

在上一个资金期间进行的遗传分析定义了两个阶段，其中缺口信号播放在肾脏生物学中的重要作用。 Notch的第一个基本功能是在肾单位分割期间。 NOTCH2信号阻止远端身份并促进近端小管（PT）和Podocyte（POD）身份单元自主或在邻近细胞中诱导它们。仅需要暂时需要此活动 S形体（SB）形成后可分配。 Notch信号的第二个重要功能是充当成年期间肾小管上皮稳态的看门人；在缺席的情况下，囊肿和肾脏功能障碍在大量囊肿中自发发育，其中一些囊肿含有继续分裂和发展乳头状腺瘤的细胞，被认为是乳头状肾脏的前体细胞癌（PRCC）。损伤增加了囊肿和乳头状腺瘤形成的频率。而这些发现解释了为什么人类减少Notch2信号导致Alagille综合征（AGS），并建议此类患者中提升Notch1活动的提高应改善健康，它们无法确定是否/如何缺陷信号指导PT和POD命运的获取。我们将利用细胞谱系跟踪工具在上一个资金期间准备，以解决有关蜂窝组织是否在 SB，在Notch2激活时，成人的肾单位子结构的组织是基础肾单位并绘制成人损伤中脱离肾脏PT的潜在。这些命运映射研究将使我们能够询问是否会命名为notch活性的SB细胞成为PT，POD，或两者都不是，如果是脱节的成年肾上皮细胞是命运限制的或寡可以的。这结果将指导我们随后搜索能够增强受伤的POD和PT再生的基因成年人。在AIM 2中，我们将询问这些细胞如何获得命运。在AIM 3中，我们将确定机械 Notch损失对成人囊肿和腺瘤形成的贡献。在AIM 4中，我们将制定策略瞬时增加AGS和PRCC的Notch1活动，其转化目标是开发临床旨在补偿AG中缺口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.