Mechanisms of Chemotherapy Induced Cognitive Defects

描述(申请人提供)：本申请的重点是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，由于治疗导致的认知障碍，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，在那里我学习了线粒体和脑瘤生物学。在过去的几年里，我认识到了化疗引起的认知缺陷的重要性，并热衷于寻找这种主要病理的生物学解释。答：这项提案的具体目标将集中在两种在肿瘤学中广泛使用的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发学习和记忆障碍的机制。这些研究的最终目标将是预防或抵消这些不利影响。目的1)利用体外培养系统测定神经前体细胞和成熟神经元对临床相关剂量顺铂和替莫唑胺的相对易感性。目的2)确定顺铂和替莫唑胺损伤神经细胞的机制，检测这些机制是否涉及线粒体功能障碍。目的3)观察急性和慢性递增剂量顺铂和替莫唑胺对活体易损神经元的影响，并探讨这种细胞损伤在学习记忆障碍中的作用。目的4)研究化疗引起的认知功能障碍是否可以通过增加神经发生和树突棘生长/稳定性的干预措施来改善，即使用Ampakines增强BDNF。我的职业计划是在加州大学欧文分校提供的培养环境中进行建议的研究。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)，我的支持性主席和院长，保护的研究时间，以及与我的临床同事的出色合作。我的直接职业目标是让自己沉浸在尖端神经科学中，这将有助于我理解癌症治疗影响大脑的机制。这将通过基础神经科学课程、动手方法、实验室会议、全国会议和密集的自学来实现。我的长期目标是在我的实验室担任高级职位，获得出版成果所需的技能，扩大我的研究团队，成功申请R01资金，并获得终身教职。最后，我想加强我在神经科学界的参与，并产生一个独立的、创造性的、转化性的研究计划。总而言之，我的目标是开展尖端的床边研究，重点研究化疗引起的显著认知缺陷背后的生物学机制，并扭转这一过程。这笔赠款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人员。 与公共健康相关：化疗药物导致的学习和记忆缺陷正迅速成为主要的临床问题，因为美国每年有150万人被诊断为癌症，其中超过60%的人现在存活了20年或更长时间。化疗药物可能通过几种潜在的机制影响认知功能，例如杀死敏感的神经前体细胞(干细胞)或损伤现有的神经元，特别是参与学习和记忆形成的脑细胞的脆弱部分(树突和树突)。这项提案的具体目标集中在两种在癌症治疗中广泛使用的药物上，并探索它们引发学习和记忆缺陷的潜在机制，最终目标是通过可用于临床的干预措施来预防或抵消癌症治疗的这些不良影响。

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. PUBLIC HEALTH RELEVANCE: Learning and memory defects induced by chemotherapeutic drugs are rapidly emerging as major clinical problem, as one and a half million people are diagnosed with cancer every year in the US, and more than 60% of these now survive for 20 years or more. Chemotherapeutic drugs may affect cognitive function via several potential mechanisms, such as killing sensitive neural progenitor cells (stem cells) or injuring existing neurons, especially the vulnerable parts of brain cells that are involved in learning and memory formation (dendrites and dendritic spines). The specific aims of this proposal focus on two medications used widely in cancer care and explore the potential mechanisms by which they provoke learning and memory defects, with the ultimate goal to prevent or counteract these adverse effects of cancer therapy with interventions that can be used in the clinic.