The Role of Suppressor of Fused in Neural Stem Cells and its Implications in Tumorigenesis

融合抑制剂在神经干细胞中的作用及其在肿瘤发生中的意义

• 批准号: 10011994
• 负责人: Odessa Yabut
• 金额: $ 9.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011994
• 关键词: Address; Advisory Committees; Behavior; Biological Assay; Brain; Brain Neoplasms; Cell Count; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cells; Cerebral Neoplasm; Critical Thinking; Defect; Doctor of Medicine; Doctor of Philosophy; Embryo; Exhibits; Forebrain Development; Functional disorder; Glioblastoma; Glioma; K-Series Research Career Programs; Knockout Mice; Knowledge; Lead; Learning; Malignant Neoplasms; Mediating; Mentors; Mentorship; Molecular; Mus; Mutation; Neocortex; Neurons; Oncogenic; Pathway interactions; Phenotype; Play; Population; Primitive Neuroectodermal Tumor; Proliferating; Property; Prosencephalon; Protein p53; Regulation; Reporting; Research; Research Institute; Role; SHH gene; Scientist; Signal Pathway; Stem Cell Development; Stem cells; TP53 gene; Techniques; Tumor Suppressor Genes; Tumor Suppressor Proteins; career; cell behavior; cell type; embryonic stem cell; experimental study; hindbrain; inhibitor/antagonist; interest; medulloblastoma; nerve stem cell; oligodendrocyte precursor; pleasure; postnatal; precursor cell; progenitor; skills; smoothened signaling pathway; stem; stem cell biology; stem cell population; subventricular zone; success; therapy development; tumor; tumor initiation; tumorigenesis; tumorigenic

PROJECT SUMMARY/ABSTRACT This proposal will investigate how Sufu regulates neural stem cell behavior and its implications in tumorigenesis. In particular, the role of Suppressor of Fused (Sufu), a tumor suppressor gene and a critical negative regulator of Shh signaling, will be examined in the postnatal neural stem cell (NSC) population. Preliminary studies show that conditional deletion of Sufu results in abnormal proliferation of NSC in the subventricular zone (SVZ) of the embryonic and postnatal forebrain. Also, experiments also showed that Sufu interacts with the tumor suppressor, p53. These findings indicate that Sufu plays an important role in regulating cell number in the progenitor zones. The aims below will investigate how Sufu regulates p53 to influence NSC behavior and determine how this might contribute to the formation of tumors in the forebrain. The questions that will be addressed in this proposal are as follows: Aim 1: Does Sufu regulate the proliferation of specific stem cell lineages within the postnatal SVZ? Aim 2: Does Sufu directly regulate p53 activity in the embryonic and postnatal SVZ? Aim 3: In the absence of p53, will loss of Sufu in NSCs lead to tumor formation? The applicant, Odessa Yabut, Ph.D., is a Postdoctoral Scholar who plans to develop an independent research career focusing on NSC and tumor formation. Dr. Yabut will take advantage of the opportunities offered by the Career Development Award to deepen her knowledge of NSC biology in the postnatal brain and begin in-depth studies on brain tumors at UCSF, a premier research institute devoted to the success of its postdoctoral scholars. Dr. Yabut will also learn a set of new skills, techniques, and collaborative opportunities. Dr. Yabut will conduct these studies under the mentorship of Samuel Pleasure, M.D., Ph.D., who is an established scientist in forebrain development. Anders Persson, Ph.D., an expert in brain tumors, will act as a co-mentor. She will also have an advisory committee composed of David Rowitch, M.D., Ph.D. and Daniel Lim, M.D., Ph.D, who are experts in NSC development and tumorigenesis. With Dr. Pleasure and her advisory committee, Dr. Yabut will enhance her knowledge on the mechanisms governing NSC development and brain tumors, hone her critical thinking skills, and help in her transition as an independent academic scientist.

项目总结/摘要 这项提案将研究腐乳如何调节神经干细胞的行为及其在 肿瘤发生特别是，融合抑制因子（Sufu），一种肿瘤抑制基因和一种关键的 Shh信号传导的负调节子，将在出生后神经干细胞（NSC）群体中进行检查。 初步研究表明，Sufu的条件性缺失可导致神经干细胞的异常增殖。 脑室下区（SVZ）的胚胎和出生后前脑。此外，实验还表明， 与肿瘤抑制因子p53相互作用。这些结果表明，腐乳发挥了重要作用， 调节祖细胞区的细胞数量。下面的目的将探讨腐乳如何调节p53， 影响神经干细胞的行为，并确定这可能如何有助于前脑肿瘤的形成。 本提案将处理的问题如下： 目的1：腐乳是否调节出生后SVZ内特定干细胞谱系的增殖？ 目的2：腐乳是否直接调节胚胎和出生后SVZ中p53的活性？ 目的3：在p53缺失的情况下，神经干细胞中Sufu的缺失是否会导致肿瘤的形成？ 申请人敖德萨雅布特博士，是一个博士后学者谁计划开发一个独立的 研究生涯专注于NSC和肿瘤形成。雅布特博士会利用这个机会 提供的职业发展奖，以加深她的NSC生物学在产后大脑的知识， 开始深入研究脑肿瘤在加州大学旧金山分校，一个首屈一指的研究机构，致力于成功的， 博士后学者Yabut博士还将学习一系列新的技能，技术和合作机会。 博士Yabut将在医学博士Samuel Pleasure的指导下进行这些研究，哲学博士、谁是 在前脑发育方面的知名科学家安德斯·罗森博士，一位脑肿瘤方面的专家， 共同导师她还将有一个由医学博士大卫罗维奇组成的咨询委员会，博士还有丹尼尔·林 医学博士，博士，他们是神经干细胞发育和肿瘤发生方面的专家。快乐博士和她的顾问 委员会，Yabut博士将提高她对NSC发展和大脑管理机制的认识。 肿瘤，磨练她的批判性思维能力，并帮助她过渡到一个独立的学术科学家。