Mechanisms of Chemotherapy Induced Cognitive Defects

化疗引起认知缺陷的机制

• 批准号: 8636500
• 负责人: Daniela Annenelie Bota
• 金额: $ 17.51万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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/8636500
• 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

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.

描述（申请人提供）：本申请重点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出患有癌症，其中 60% 以上的人现在可以存活 20 年，但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，在实验室拥有扎实的背景，我在那里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，并热衷于寻找这种主要病理学的生物学解释。 A. 该提案的具体目标将集中在肿瘤学中广泛使用的两种 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) 使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。目标 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群体的影响，并研究这种细胞损伤在学习和记忆缺陷中的作用。目标 4) 检查是否可以通过增强神经发生和树突棘生长/稳定性的干预措施（即使用安帕金增强 BDNF）来改善化疗引起的认知缺陷。 B. 我的职业计划是在加州大学欧文分校提供的培育环境中进行拟议的研究。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，一位国际肿瘤学领导者（Frank Meyskens 教授），我的支持主席和院长，受保护的研究时间，以及我的临床同事的出色合作。 我近期的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、实践方法、实验室会议、全国会议和强化自学来完成。我的长期目标是在我的实验室中担任高级职务，获得富有成效的出版物所需的技能，扩大我的研究团队，成功申请 R01 资助并获得终身教职。最后，我想加强对神经科学界的参与，并制定一个独立的、创造性的、转化性的研究项目。 总之，我的目标是开发前沿的临床研究，重点关注化疗引起的显着认知缺陷的生物学机制，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员。