Mechanisms of Chemotherapy Induced Cognitive Defects

描述（由申请人提供）：本申请主要研究化疗药物影响癌症患者认知功能的机制。每年有数百万人被诊断患有癌症，其中60%以上的人现在存活了20年，由于治疗引起的认知障碍，生活质量严重下降。我是一名训练有素的神经肿瘤学家，在实验室有扎实的背景，在那里我研究了线粒体和脑肿瘤生物学。在过去的几年里，我认识到化疗引起的认知缺陷的重要性，并开始热衷于寻找这一主要病理的生物学解释。A.该提案的具体目标将集中在两种广泛用于肿瘤学的dna靶向化合物-顺铂和替莫唑胺；我们的目标是探索这些药物引起学习和记忆缺陷的机制。这些研究的最终目标是预防或抵消这些不利影响。目的1)利用体外系统确定神经祖细胞和成熟神经元对临床相关剂量的顺铂和替莫唑胺的相对脆弱性。目的2)确定顺铂和替莫唑胺损伤神经元细胞群的机制，测试这些机制是否涉及线粒体功能障碍。目的3)研究急性和慢性分级顺铂和替莫唑胺剂量对体内易损神经元群的影响，并研究这种细胞损伤在学习和记忆缺陷中的作用。目的4)检查化疗诱导的认知缺陷是否可以通过增强神经发生和树突脊柱生长/稳定性的干预来改善，即使用ampakines增强BDNF。B.我的职业规划是在加州大学欧文分校提供的培养环境中进行我所提出的研究。这包括我的导师，一位国际知名的神经科学家/临床医生（Tallie Z. Baram教授），我的共同导师，肿瘤学的国际领导者（Frank Meyskens教授），支持我的主席和院长，保护研究时间，以及来自临床同事的出色合作。我最近的职业目标是让自己沉浸在尖端的神经科学中，这将有助于我理解癌症治疗对大脑的影响机制。这将通过基础神经科学课程、实践方法、实验室会议、全国会议和密集的自学来完成。我的长期目标是在我的实验室担任高级职位，获得出版高产论文所需的技能，扩大我的研究小组，成功申请R01基金并获得终身教职。最后，我想加强我在神经科学社区的参与，并产生一个独立的，创造性的，转化的研究项目。总之，我的目标是开展前沿的从实验到临床的研究，重点研究化疗引起的显著认知缺陷的生物学机制，并逆转这一过程。这笔资助将为我提供必要的资金和指导，使我成为一名成功的独立研究员。

DESCRIPTION (provided by applicant): This application is focused on the study of the mechanisms by which chemotherapeutic drugs impact the cognitive function of cancer patients. Millions of people are diagnosed with cancer every year, and more than 60% of these now survive for 20 years, with severely diminished quality of life due to treatment-induced cognitive impairments. I am a fully trained neuro-oncologist, with a solid background in the lab, where I studied both mitochondrial and brain tumor biology. Over the past years, I recognized the importance of chemotherapy- induced cognitive defects and became passionate about finding the biological explanations for this major pathology. A. The specific aims of this proposal will focus on two DNA-targeting compounds that are widely used in oncology - cisplatin and temozolomide; we aim to explore the mechanisms by which these drugs provoke learning and memory defects. The ultimate goal of these studies would be to prevent or counteract these adverse effects. Aim 1) To determine the relative vulnerability of neural progenitor cells and mature neurons to clinically-relevant doses of cisplatin and temozolomide, using in vitro systems. Aim 2) To determine the mechanism by which cisplatin and temozolomide injure neuronal cell populations, testing if these mechanisms involve mitochondrial dysfunction. Aim 3) To examine the effects of acute and chronic graded cisplatin and temozolomide doses on vulnerable neuronal populations in vivo, and to study the role of this cellular injury in learning and memory defects. Aim 4) To examine if chemotherapy-induced cognitive deficits can be ameliorated by an intervention that augments neurogenesis and dendritic spine growth / stability, i.e., BDNF enhancement using ampakines. B. My career plan is to conduct the research proposed in the nurturing environment offered by the University of California, Irvine. This includes my mentor, an internationally known neuroscientist/clinician (Prof. Tallie Z. Baram), my co-mentor, an international leader in oncology (Prof. Frank Meyskens), my supportive chair and dean, protected research time, and excellent collaboration from my clinical colleagues. My immediate career goal is to immerse myself in cutting-edge neuroscience that will facilitate my understanding of the mechanisms by which cancer treatments impact the brain. This will be accomplished via basic neuroscience courses, hands-on methods, lab meetings, national meetings and intensive self-study. My long-term goals are to assume a senior role in my lab, acquire the skills necessary for productive publications, enlarge my research group, apply successfully for R01 funding and receive tenure. Finally, I want to enhance my involvement in the neuroscience community and to generate an independent, creative, translational research program. In summary, my goal is to develop cutting-edge bench-to bedside research focused on the biological mechanisms underlying the prominent cognitive deficits caused by chemotherapy, and to reverse this process. This grant will provide me with the necessary funding and mentorship to become a successful, independent researcher.