Aerobic glycolysis regulates apoptosis in neurogenesis and medulloblastoma

描述（由申请人提供）：本提案的主要目标是使Timothy Gershon博士能够发展一种学术生涯，强调转化实验室研究，重点关注他在儿科神经肿瘤临床工作中遇到的问题的基本神经发育研究技术。具体而言，Gershon博士将专注于髓母细胞瘤的发病机制和新型生物抗肿瘤治疗的发展。Gershon博士将在北卡罗来纳州（北卡罗来纳州），查佩尔山，在那里他开始了2009年7月31日终身教职的位置指导。主要导师Mohanish Deshmukh博士，将领导K08导师计划Deshmukh博士是神经发育中细胞凋亡调控的领先专家，最近专注于脑肿瘤中细胞凋亡的逃避。Deshmukh博士在出版物、资助和指导年轻研究人员方面有着良好的记录。他为Gershon博士制定了一个全面的指导计划，主要专注于开发使用基因工程小鼠的实验专业知识，以及细胞凋亡和代谢过程的分子解剖。研究将集中在小脑神经发生的中断，促进神经祖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，它起源于人类和小鼠的小脑颗粒神经元祖细胞。Gershon博士利用基因工程改造成易患成神经管细胞瘤和缺乏凋亡的小鼠，为一个非常新颖的假设开发了初步数据：有氧糖酵解和逃避凋亡是相互关联的过程，是正常神经发生的组成部分，并在成神经管细胞瘤中被吸收。通过他的具体目标，Gershon博士将测试这一假设及其治疗意义，开发糖酵解抑制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博士组成的科学咨询委员会。每周与Deshmukh博士会面，每季度与咨询委员会会面，Gershon博士将有机会不断获得神经科学，癌症生物学和神经肿瘤学经验丰富的专家的反馈和建议。这种专家监督将使候选人联合收割机结合他以前学到的和完成的详细和高度集中的实践研究经验，适应神经科学的方法，以髓母细胞瘤。导师制，教学法和研究建议沿着由NIH提供的学术和研究基础设施将确保候选人成功过渡到NIH资助的独立调查员。

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.