Sex Differences in Alcohol Use Disorder Neurodegeneration using Multimodal PET and DTI Neuroimaging

项目摘要/摘要 此K01申请表中描述的研究和培训计划将为应聘者提供 成为了解神经变性性别差异的独立研究人员所需的技能 (即小胶质细胞和白质束)和酒精使用障碍(AUD)的神经认知来识别新的 针对性别差异的治疗目标。这个五年计划的研究部分涉及 正电子发射断层扫描(PET)在神经认知功能性别差异研究中的应用 AUD患者小胶质细胞水平性别差异的基础功能；(2)扩散张量磁共振 成像(DTI)检查AUD患者白质束完整性的性别差异；(3)PET和DTI 多峰综合分析确定小胶质细胞水平与白质束之间的关系 女性和男性AUD患者的完整性和神经认知功能。60只(15只雄性和15只雌性) 对于AUD和30名年龄、性别和吸烟相匹配的健康对照组，将同时参加PET和DTI 扫描以促进PET、DTI和PET/DTI集成分析。为了系统地识别性别差异 对于白质束完整性的模式，候选人还将检查来自大型、存档、 神经成像DTI数据集(人类连接体项目)，以在 数据收集。这种新颖的数据收集和二次数据分析的组合旨在 通过提供以下两方面的实践经验，最大限度地提高候选人的培训：(1)理论和行为 她自己在公认专家的指导下进行的联合多模式神经成像研究；以及，(2) 对大规模神经影像数据集的分析和解释。为了追求这些目标，候选人 建议在四个主要领域开展进一步的培训：(1)澳门氏症的神经生物学，(2)治疗 AUD的结果研究和临床相关性，(3)DTI和多模式神经成像，(4)生物统计学 接近了。K01机制提供的机会将使候选人能够开始 严格的、有组织的5年培训和研究计划，旨在为她提供必要的技能 在上面强调的四个领域。这个学习计划将结合正规的教学课程，指导 阅读资料、一对一教程、专业研讨会、出席科学研究会议，以及 有指导的研究经验。K01中提出的研究和培训提供了一个理想的 跨学科机会实现候选人成为独立人士的长期职业目标 科学家，在澳大利亚的神经生物学中将性作为一个生物变量加以特别关注。这支队伍 导师和合作者是这些领域的领导者，与激励和合作的 耶鲁医学院的环境，将促进候选人的成长，并为她的 独立从事澳大利亚大学神经科学和神经影像研究的工作。

Project Summary/Abstract The program of research and training described in this K01 application will provide the candidate with the requisite skills to become an independent investigator understanding sex differences in neurodegeneration (i.e., microglia and white matter tracts) and neurocognition in alcohol use disorder (AUD) to identify novel treatment targets that address sex differences. The research component of this 5-year plan involves the application of: (1) positron emission tomography (PET) imaging to examine sex differences in neurocognitive function that underlie sex differences in microglia levels in AUD; (2) diffusion tensor magnetic resonance imaging (DTI) to examine sex differences in white matter tract integrity in AUD and; (3) PET and DTI multimodal integration analysis to determine the relationship between microglia levels, white matter tract integrity, and neurocognitive function in women and men with AUD. Sixty (15 male and 15 female) individuals with AUD and 30 age-, sex-, and smoking-matched healthy controls will participate in both PET and DTI scanning to facilitate PET, DTI, and PET/DTI integration analysis. To systematically identify sex differences in patterns of white matter tract integrity, the candidate will also examine data from a large, archived, neuroimaging DTI dataset (The Human Connectome Project), to generate publications and productivity during data collection. This combination of novel data collection and secondary data analyses is designed to maximize the candidate's training via provision of hands-on experience in both: (1) the theory and conduct of her own combined multimodal neuroimaging study under guided supervision of recognized experts; and, (2) the analysis and interpretation of large-scale neuroimaging datasets. In pursuit of these goals, the candidate proposes to undertake further training in four primary areas: (1) the neurobiology of AUD, (2) treatment outcomes research and clinical corelates of AUD, (3) DTI and multimodal neuroimaging, and (4) biostatistical approaches. The opportunities afforded by the K01 mechanism would enable the candidate to embark on a rigorous, structured 5-year program of training and research, designed to provide her with the necessary skills in the four areas highlighted above. This program of study will combine formal didactic courses, directed readings, one-on-one tutorials, specialized workshops, attendance of scientific research conferences, and mentored research experience. The research and training proposed in this K01 provides an ideal interdisciplinary opportunity to achieve the candidate's long-term career goal of becoming an independent scientist with a particular focus on sex as a biological variable in the neurobiology of AUD. The team of mentors and collaborators are leaders in these fields and, together with the stimulating and collaborative environment of the Yale School of Medicine, will facilitate the candidate's growth and prepare her for an independent career at the interface of AUD neuroscience and neuroimaging research.