Mechanisms of Chemotherapy Induced Cognitive Defects

化疗引起认知缺陷的机制

基本信息

批准号：
8237301
负责人：
Daniela Annenelie Bota
金额：
$ 17.06万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8237301
关键词：
Acute Adult Adverse effects Affect Animals Atrophic Biological Brain Brain Neoplasms Brain-Derived Neurotrophic Factor California Cancer Patient Cell Density Cell Survival Cells Chronic Cisplatin Clinic Clinical Clinical Trials Cognitive Cognitive deficits Collaborations Communities DNA DNA Damage Data Defect Dendrites Dendritic Spines Diagnosis Dose Elements Environment Functional disorder Funding Genetic Transcription Goals Golgi Apparatus Grant Growth Hippocampus (Brain)Impaired cognition In Vitro Individual International Intervention Label Learning Life Malignant Neoplasms Memory Mentors Mentorship Metabolism Methods Mitochondria Mitochondrial DNA Neuronal Injury Neurons Neurosciences Nuclear Oncologist Pathology Pharmaceutical Preparations Population Process Publications Pyramidal Cells Quality of life Rattus Relative (related person)Research Research Personnel Role Solid Staining method Stains Stem cells Synapses System Testing Time Training Translational Research Tumor Biology Universities Vulnerable Populations Work bench to bedside brain cell cancer care cancer therapy career cell injury chemotherapeutic agent chemotherapy clinically relevant cognitive function density hippocampal pyramidal neuron improved in vivo injured killings meetings mitochondrial dysfunction nerve stem cell nestin protein neurogenesis oncology prevent programs relating to nervous system respiratory enzyme skills stem temozolomide

项目摘要

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.

描述（由申请人提供）：该应用集中在化学治疗药物影响癌症患者认知功能的机制上。每年有数百万人被诊断出患有癌症，其中超过60％的人现在生存了20年，由于治疗引起的认知障碍，生活质量严重降低。我是一位受过全面训练的神经肿瘤学家，在实验室中具有坚实的背景，在那里我研究了线粒体和脑肿瘤生物学。在过去的几年中，我认识到化学疗法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：该提案的具体目的将集中于两种靶向DNA靶向化合物，这些化合物广泛用于肿瘤学 - 顺铂和替莫唑胺。我们旨在探索这些药物会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良影响。目标1）使用体外系统，确定神经祖细胞和成熟神经元与临床上剂量相关的顺铂和替莫唑胺的相对脆弱性。目标2）确定顺铂和替莫唑胺会损害神经元细胞群体的机制，测试这些机制是否涉及线粒体功能障碍。目标3）检查急性和慢性分级顺铂和替莫唑胺剂量对体内脆弱神经元种群的影响，并研究这种细胞损伤在学习和记忆缺陷中的作用。目标4）检查化学疗法诱导的认知缺陷是否可以通过增加神经发生和树突状脊柱生长 /稳定性的干预来改善，即使用宽松的BDNF增强。 B.我的职业计划是在加利福尼亚大学尔湾分校提供的培养环境中进行的研究。其中包括我的导师，国际知名的神经科学家/临床医生（Tallie Z. Baram教授），我的同事，国际肿瘤学的国际领导者（Frank Meyskens教授），我的支持主席和Dean，受保护的研究时间，以及来自我的临床同事的出色合作。我的直接职业目标是将自己沉浸在尖端的神经科学中，这将有助于我对癌症治疗影响大脑的机制的理解。这将通过基本的神经科学课程，动手方法，实验室会议，全国会议和密集的自学来完成。我的长期目标是在我的实验室中扮演高级角色，获得生产性出版物所需的技能，扩大我的研究小组，成功申请R01资金并获得任期。最后，我想加强对神经科学社区的参与，并制定独立，创造性的转化研究计划。总而言之，我的目标是开发尖端的基准床边研究，该研究重点介绍了由化学疗法引起的明显认知缺陷的生物学机制，并扭转了这一过程。这笔赠款将为我提供必要的资金和指导，以成为一名成功的独立研究人员。公共卫生相关性：化学治疗药物引起的学习和记忆缺陷正在迅速成为主要的临床问题，因为在美国，每年一百万人被诊断出患有癌症，其中超过60％的人现在存活20年或更长时间。化学治疗药物可能会通过多种潜在的机制（例如杀死敏感的神经祖细胞（干细胞））或损害现有神经元的伤害，尤其是与学习和记忆形成有关的脑细胞的脆弱部位（树突状和树突状刺）。该提案的具体目的集中于两种在癌症护理中广泛使用的药物，并探讨了它们引起的学习和记忆缺陷的潜在机制，其最终目标是防止或抵消诊所中可用于使用干预措施的癌症治疗的这些不良影响。