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

项目摘要/摘要 这项提案将调查Sufu如何调节神经干细胞的行为及其在 肿瘤发生学。尤其是融合抑制基因(Sufu)的作用，它是一种肿瘤抑制基因，也是一种关键的 Shh信号的负调控，将在出生后的神经干细胞(NSC)群体中进行检测。 初步研究表明，Sufu的条件性缺失会导致NSC的异常增殖 胚胎和出生后前脑的脑室下区(SVZ)。此外，实验还表明，素福 与肿瘤抑制因子P53相互作用。这些发现表明，腐乳在人体内起重要作用。 调节祖细胞带中的细胞数量。下面的目标将调查素福如何调节P53以 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。 这项提案将涉及的问题如下： 目的1：Sufu对出生后SVZ内特定干细胞系的增殖有调节作用吗？ 目的2：Sufu是否直接调节胚胎和出生后SVZ的P53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？ 申请人是敖德萨·雅布特博士，他是一名博士后学者，计划开发一种独立的 专注于神经干细胞和肿瘤形成的研究生涯。雅布特博士将利用这个机会 由职业发展奖提供，以加深她在出生后大脑中的NSC生物学知识和 在加州大学旧金山分校开始深入研究脑瘤，这是一家致力于ITS成功的顶级研究机构 博士后学者。雅布特博士还将学习一系列新的技能、技术和合作机会。 雅布特博士将在塞缪尔·普莱斯的指导下进行这些研究，塞缪尔·普莱斯是一名医学博士， 前脑发育方面的知名科学家。脑瘤专家安德斯·佩尔松博士将担任 共同导师。她还将有一个由David Rowitch，医学博士和Daniel Lim组成的顾问委员会， 医学博士，博士，他们是神经干细胞发展和肿瘤发生方面的专家。带着愉悦博士和她的建议 雅布特博士将增进她对神经干细胞发育和脑的调控机制的知识 肿瘤，磨练她的批判性思维能力，并帮助她过渡为一名独立的学术科学家。

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.