Understanding How Ciliary Hedgehog Signaling Causes Medulloblastoma

项目摘要/摘要 这项提议的目标是培养大卫·R·罗利，医学博士，博士，一名具有 打好基础科学研究基础，成为脑科学的独立研究者 肿瘤生物学。这项拟议的研究还旨在改善对患有糖尿病的患者的治疗。 髓母细胞瘤，一种常见的儿童脑癌。建议的研究内容包括 阻碍髓母细胞瘤患者治疗进步的局限性 识别新的、可用药的靶点，这些靶点通过 初级纤毛。候选人的中心假设是氧固醇合成酶HSD11β2 产生纤毛氧固醇，激活Hedgehog信号并诱导CDK6驱动 不受控制的细胞增殖。这项工作将阐明(1)致癌的HH信号是如何 转导以促进细胞生长；以及(2)阻断该信号是否有效 HH相关性髓母细胞瘤的治疗策略。为了实现这些目标，以下是 提出了具体的目标：(1)确定Hsd11β2对睫状刺猬的作用 以及(2)确定Hedgehog信号如何在髓母细胞瘤中失活CDK6。这个 候选人的培训和研究计划结合了课程作业、研讨会、 指导和实践研究经验设置在卓越的学术环境中 加州大学旧金山分校，一个卓越的医学和研究中心，被赋予了一个 临床医生和科学家的社区。候选人的导师是杰里米·赖特博士，一位 公认的小鼠遗传模型和分子机制方面的专家和先驱 脊椎动物刺猬通过初级纤毛发出信号，无论是在发育中还是在癌症中。 候选人的多学科咨询委员会包括杰出的科学家 该奖项的研究战略所涵盖的所有领域的专业知识。成功完成 拟议的研究将为测试特定的靶向提供令人信服的临床前理论基础。 生物标记物定义的Hedgehog相关亚群患者中的抑制剂 髓母细胞瘤。中期目标是让候选人获得知识， 提交一份成功的R01提案所需的技术技能和专业知识。长期目标 是为Hedgehog相关髓母细胞瘤的综合临床前平台开发的 在这项建议中，告知治疗决定并提高髓母细胞瘤患者的存活率。

PROJECT SUMMARY/ABSTRACT The objective of this proposal is to train David R. Raleigh, MD, PhD, a candidate with an excellent foundation for basic science research, to become an independent investigator of brain tumor biology. The proposed research also aims to improve treatments for patients with medulloblastoma, a common pediatric brain cancer. The proposed research addresses limitations that have hindered therapeutic advancements for patients with medulloblastoma by identifying novel, druggable targets that transduce oncogenic Hedgehog signaling via the primary cilium. The candidate's central hypothesis is that the oxysterol synthase Hsd11β2 generates ciliary oxysterols that activate Hedgehog signaling and induce Cdk6 to drive uncontrolled cell proliferation. This work will elucidate (1) how oncogenic Hh signaling is transduced to cause cell growth; and (2) whether blocking this signaling is an effective therapeutic strategy for Hh-associated medulloblastoma. Toward those goals, the following specific aims are proposed: (1) determine how Hsd11β2 contributes to ciliary Hedgehog signaling; and (2) define how Hedgehog signaling misactivates Cdk6 in medulloblastoma. The candidate's training and research plan incorporates a combination of coursework, workshops, mentoring, and hand-on research experience set in the outstanding academic environment of UCSF, a center of excellence in medicine and research endowed with a well-integrated community of clinicians and scientists. The candidate's mentor is Dr. Jeremy Reiter, a recognized expert and pioneer in mouse genetic models and the molecular mechanisms of vertebrate Hedgehog signaling through the primary cilium., both in development and in cancer. The candidate's multidisciplinary advisory committee includes distinguished scientists with expertise in all areas covered by the research strategy of this award. Successful completion of the proposed research will produce compelling preclinical rationale for testing specific targeted inhibitors in patients within biomarker-defined subsets of Hedgehog-associated medulloblastoma. The intermediate-term goal is for the candidate to acquire the knowledge, technical skill and expertise necessary to submit a successful R01 proposal. Long-term goals are for the integrated, preclinical platform of Hedgehog-associated medulloblastoma developed in this proposal to inform treatment decisions and improve survival of medulloblastoma patients.