Aerobic glycolysis regulates apoptosis in neurogenesis and medulloblastoma

描述(由申请人提供)：这项建议的主要目标是使Timothy Gershon博士能够发展他的学术生涯，强调转化性实验室研究，专注于基础神经发育研究技术，解决他在儿科神经肿瘤学临床工作中遇到的问题。具体地说，Gershon博士将专注于髓母细胞瘤的发病机制和基于生物的新型抗肿瘤疗法的开发。Gershon博士将在北卡罗来纳大学(UNC)教堂山分校接受指导，他于2009年7月31日开始在那里担任终身教职。主要导师Mohanish Deshmukh博士将领导这项K08导师计划。德什穆克博士是神经发育中细胞凋亡调控方面的领先专家，最近专注于脑肿瘤细胞凋亡的规避。德什穆克博士在发表论文、资助和指导年轻研究人员方面有着良好的记录。他为格尔森博士制定了一项全面的指导计划，主要专注于开发使用基因工程小鼠的实验专业知识，以及对细胞凋亡和代谢过程的分子解剖。研究将集中在破坏小脑神经发生，促进神经前体细胞增殖形成髓母细胞瘤。髓母细胞瘤是儿童最常见的恶性脑肿瘤，起源于人和小鼠的小脑颗粒神经前体细胞。Gershon博士利用基因工程培育的易患髓母细胞瘤和缺乏细胞凋亡的小鼠，为一个非常新的假说提供了初步数据：有氧糖酵解和逃避凋亡是相互关联的过程，是正常神经发生不可或缺的部分，并与髓母细胞瘤有关。通过他的具体目标，Gershon博士将测试这一假设及其治疗意义，开发抑制糖酵解作为髓母细胞瘤的创新治疗方法。为了最大限度地利用他的培训经验，Gershon博士组建了一个由William Snider博士、Albert Baldwin博士和Matt Ewend博士组成的北卡罗来纳大学科学顾问委员会。Gershon博士每周与Deshmukh博士会面，每季度与咨询委员会会面，他将不断有机会从神经科学、癌症生物学和神经肿瘤学方面的经验丰富的专家那里获得反馈和建议。这种专家监督将使候选人能够将他以前所学到的和所取得的成就与详细和高度集中的实践研究经验结合起来，采用神经科学的方法来治疗髓母细胞瘤。北卡罗来纳大学提供的导师、教学和研究提案以及学术和研究基础设施将确保候选人成功过渡到NIH资助的独立研究员。

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.