Aerobic glycolysis regulates apoptosis in neurogenesis and medulloblastoma

有氧糖酵解调节神经发生和髓母细胞瘤中的细胞凋亡

基本信息

批准号：
8433510
负责人：
Timothy Gershon
金额：
$ 17.66万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433510
关键词：
Advisory Committees Animal Model Apoptosis Apoptotic Biology Brain Brain Neoplasms Cancer Biology Cell Death Cerebellar Neoplasms Cerebellum Child Childhood Clinical Cytoplasmic Granules Data Development Disabled Persons Dissection Doctor of Philosophy Ensure Enzymes Erinaceidae Faculty Feedback Funding Genetic Engineering Genetically Engineered Mouse Glycolysis Glycolysis Inhibition Goals Growth Head Hexokinase 2 Human Intervention Investigation Knock-out Knockout Mice Knowledge Laboratories Learning Life Link Malignant Neoplasms Malignant neoplasm of brain Measures Mediating Mentors Mentorship Metabolic Metabolic Control Metabolism Molecular Morbidity - disease rate Mus Mutation Neurons Neurosciences North Carolina Oncogenic Pathogenesis Patients Play Population Positioning Attribute Process Proliferating Publications Regulation Research Research Infrastructure Research Personnel Research Proposals Research Technics Role Signal Transduction Survivors Tamoxifen Techniques Testing Therapeutic Toxic effect Training United States National Institutes of Health Universities Work aerobic glycolysis base cancer therapy career cytotoxic experience in vivo innovation insight medulloblastoma meetings nerve stem cell neuro-oncology neurodevelopment neurogenesis novel postnatal progenitor programs skills smoothened signaling pathway therapeutic target tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The major objective of this proposal is to enable Dr. Timothy Gershon to develop an academic career that emphasizes translational laboratory investigation focusing basic neuro-developmental research techniques on problems encountered in his clinical work in Pediatric Neuro-oncology. Specifically, Dr. Gershon will focus on the pathogenesis of medulloblastoma and the development of novel, biologically-based anti-tumor therapy. Dr. Gershon will be mentored at the University of North Carolina (UNC), Chapel Hill where he began a tenure-track faculty position on July 31st, 2009. The primary mentor, Mohanish Deshmukh, Ph.D., will head this K08 mentorship program. Dr. Deshmukh is a leading expert in the regulation of apoptosis in neural development and has recently focused on the evasion of apoptosis in brain tumors. Dr. Deshmukh has a strong track record of publications, funding, and mentoring young investigators. He has developed a comprehensive mentoring plan for Dr. Gershon, primarily focused on developing experimental expertise in the use of genetically engineered mice, and the molecular dissection of apoptotic and metabolic processes. Research will focus on disruptions of cerebella neurogenesis that promote medulloblastoma formation from proliferating neural progenitors. Medulloblastoma is the most common malignant brain tumor in children and it arises in humans and mice from cerebella granule neuron progenitors. Using mice genetically engineered to be medulloblastoma-prone and apoptosis-deficient, Dr. Gershon has developed preliminary data for a highly novel hypothesis: that aerobic glycolysis and evasion of apoptosis are interrelated processes, integral to normal neurogenesis and co-opted in medulloblastoma. Through his Specific Aims, Dr. Gershon will test this hypothesis and its therapeutic implication, developing inhibition of glycolysis as an innovative treatment for medulloblastoma. To maximize his training experience, Dr. Gershon has assembled a UNC scientific advisory committee comprised of Dr. William Snider, Dr. Albert Baldwin and Dr. Matt Ewend. Meeting weekly with Dr. Deshmukh and quarterly with the advisory committee, Dr. Gershon will have continuous opportunity to gain feedback and advice from experienced experts in Neuroscience, Cancer Biology and Neuro-oncology. This expert oversight will enable the candidate to combine what he has previously learned and accomplished with a detailed and highly focused practical research experience that adapts a neuroscience approach to medulloblastoma. The mentorship, didactics, and research proposal along with the academic and research infrastructure provided by UNC will ensure the candidate's successful transition to an NIH-funded independent investigator.

描述（由申请人提供）：该提案的主要目的是使Timothy Gershon博士能够发展一个学术职业，该职业强调转化实验室调查，重点是基本的神经发展研究技术，这些研究对他在儿科神经综合学的临床工作中遇到的问题。具体而言，Gershon博士将重点关注髓母细胞瘤的发病机理以及新型，基于生物学的抗肿瘤疗法的发展。 Gershon博士将在教堂山北卡罗来纳大学（UNC）的指导下，在那里他于2009年7月31日开始任职。 Deshmukh博士是调节神经发育中凋亡的领先专家，最近专注于逃避脑肿瘤凋亡。 Deshmukh博士在出版物，资金和指导年轻调查员方面具有良好的记录。他已经为Gershon博士制定了一项全面的指导计划，主要侧重于开发用于使用基因工程小鼠的实验专业知识，以及凋亡和代谢过程的分子解剖。研究将集中于脑神经发生的破坏，从而促进髓母细胞瘤从增生的神经祖细胞中形成。髓母细胞瘤是儿童中最常见的恶性脑肿瘤，它来自小脑颗粒神经元祖细胞的人类和小鼠。 Gershon博士使用基因设计的小鼠进行了基因工程，可作为髓母细胞瘤易发和细胞凋亡，为高度新颖的假设开发了初步数据：有氧糖糖酵解和逃避凋亡是相互关联的过程，与正常的神经发生不可或缺的过程相互关联，并在髓母细胞中进行了共同作用。通过他的具体目的，Gershon博士将检验这一假设及其治疗意义，并将抑制糖酵解作为髓母细胞瘤的创新治疗方法。为了最大程度地提高他的培训经验，Gershon博士组建了一个由William Snider博士，Albert Baldwin博士和Matt Ewend博士组成的UNC科学咨询委员会。 Gershon博士每周与Deshmukh博士举行会议，并与咨询委员会举行会议，将有机会获得神经科学，癌症生物学和神经肿瘤学专家的反馈和建议。这项专家的监督将使候选人能够将他以前学到的东西结合在一起，并具有详尽且高度专注的实践研究经验，从而适应了神经科学方法的髓母细胞瘤。 UNC提供的指导，教学和研究建议以及UNC提供的学术和研究基础设施将确保候选人的成功过渡到NIH资助的独立研究员。