ROLE OF NOTCH AND KIDNEY DEVELOPMENT

NOTCH 和肾脏发育的作用

• 批准号: 7654410
• 负责人: RAPHAEL KOPAN
• 金额: $ 44.1万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7654410
• 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; Iceberg; 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; clinically relevant; embryonic stem cell; experience; genetic analysis; improved; in vitro Model; injured; loss of function; nephrogenesis; neuronal cell body; notch protein; podocyte; progenitor; public health relevance; receptor; renal epithelium; therapy design; tool; translational approach

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: We find that mutations reducing Notch activity that do not result in developmental abnormalities nonetheless contribute to formation of cysts later in life, 30% of which will develop renal adenomas resembling human papillary renal carcinoma. Since Notch reduction therapy is being considered in adult humans, a full, mechanistic elucidation of the role Notch signaling plays during renal development and its role in maintenance of adult renal tubules continues to be of great scientific and clinical importance.

描述（由申请人提供）：在上一个资助期间进行的遗传分析定义了Notch信号在肾脏生物学中发挥重要作用的两个阶段。 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) 自主细胞身份或在邻近细胞中诱导它们。这种活动只是暂时需要的，在 S 形体 (SB) 形成后就变得可有可无。 Notch 信号的第二个重要功能是在成年期间充当肾小管上皮稳态的看门人。如果没有它们，大部分近亲繁殖动物会自发出现囊肿和肾功能障碍，其中一些囊肿含有继续分裂和发展为乳头状腺瘤的细胞，被认为是乳头状肾细胞癌（PRCC）的前身。损伤会增加囊肿和乳头状腺瘤形成的频率。虽然这些发现解释了为什么人类中 Notch2 信号减少会导致 Alagille 综合征 (AGS)，并表明提高此类患者的 Notch1 活性可以改善健康，但它们并没有确定 Notch 信号是否/如何指导 PT 和 POD 命运的获得。我们将利用上一个资助期间准备的细胞谱系追踪工具来解决Notch2激活时SB中的细胞组织是否是成体肾单位中肾单位亚结构组织的基础的问题，并绘制出成人去分化肾 PT 从损伤中恢复的潜力。这些命运图谱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，两者都不会，或两者兼而有之，以及去分化的成体肾上皮细胞是否是命运限制性的或寡能的。这些结果将指导我们后续寻找能够增强受伤成人 POD 和 PT 再生的基因。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 Notch 缺失对成人囊肿和腺瘤形成的机制贡献。在目标 4 中，我们将制定暂时增强 AGS 和 PRCC 中 Notch1 活性的策略，其转化目标是开发旨在补偿 AGS 中 Notch 信号减少的临床干预措施。公共健康相关性：我们发现，Notch 活性降低的突变不会导致发育异常，但会在以后的生活中导致囊肿的形成，其中 30% 的囊肿会发展为类似于人乳头状肾癌的肾腺瘤。由于Notch减少疗法正在考虑用于成年人，因此对Notch信号传导在肾脏发育过程中的作用及其在成人肾小管维持中的作用的全面、机制阐明仍然具有重要的科学和临床重要性。