Imaging transcriptomics across developmental stages of early psychotic illness

项目总结/摘要 作为一名神经发育研究方面的医生兼科学家， 神经科学，我寻求指导支持，以培训新的分析，以整合神经成像和分子 人类遗传学数据，在我成为独立研究者的道路上。我建议一个综合的 关注精神病临床高危青年前瞻性纵向队列（NAPLS 2）的项目 该研究利用了神经影像学分析和高通量、公开可用的全脑转录组学技术的进步， 地图集调查精神分裂症（SZ）风险的神经发育机制。先前的研究表明， 认知功能障碍是SZ的核心特征，工作记忆（WM）通常在整个过程中成熟。 青春期时，明显的临床精神病发作是最常见的，和WM依赖，部分，广泛， 分布皮层谷氨酸和GABA介导的神经回路。然而，预防和治疗 SZ的认知功能障碍有限。该项目结合了体内的横截面和纵向 来自NAPLS 2队列的神经影像学数据与公开可用的人类死后脑转录组数据 为了测试形态相似性网络和认知障碍是否在认知障碍中受到不同的影响， 发展为精神病的年轻人，这些皮质模式是否与WM的行为测量有关， 受影响的额颞区是否具有独特的谷氨酸/GABA转录物富集模式， SZ风险基因。如果这些假设得到证实，该项目将提供证据， 在明显的疾病发作之前是可检测的，并且与认知的行为和分子测量相关。 功能障碍 为了达到这些研究目标，我寻求成像基因组学和纵向分析的正式培训 方法，这是可能的，通过结构化的课程，指导从一个团队的杰出科学家， 以及加州大学洛杉矶分校在基因组学、神经影像学和精神病研究方面出色的基础设施。主要导师 (Dr.比尔登）在精神病和前瞻性纵向研究方面具有国际公认的专业知识， 相关的神经认知和神经影像表型，具有丰富的经验，作为一个成功的研究 导师核心共同导师在生物信息学和功能基因组学方面具有互补的专业知识。 Gandal）和统计遗传学方法（Pasaniuc博士）对这一提议至关重要。我的合作者（Raznahan博士） 在发育神经成像方面有着著名的专业知识一个关键的顾问（博士弗雷默）将允许共享 生物信息学资源和核心设施，以指导大规模功能和发展分析 基因组学方法，并将提供实验室领导和职业发展的重点培训。这个K 这项建议将为我提供深入的研究方法和职业支持所需的培训， 成功过渡到独立。该提案符合NIMH的战略目标， 复杂行为背后的机制，并研究整个生命周期的精神疾病轨迹。

PROJECT SUMMARY/ABSTRACT As a physician-scientist in neurodevelopmental research with a strong background in molecular neuroscience, I seek mentored support for training in novel analytics to integrate neuroimaging and molecular genetics data in humans, on my path toward becoming an independent investigator. I propose an integrative project focusing on a prospective longitudinal cohort of youth at clinical high risk (CHR) for psychosis (NAPLS2) that utilizes advances in neuroimaging analyses and high throughput, publicly available brain-wide transcriptomic atlases to investigate neurodevelopmental mechanisms of schizophrenia (SZ) risk. Prior work suggests that cognitive dysfunction is a core feature of SZ, with working memory (WM) typically maturing throughout adolescence when overt clinical psychosis onset is most common, and WM depends, in part, on widely distributed cortical glutamate- and GABA-mediated neural circuitry. However, prevention and treatment of cognitive dysfunction in SZ is limited. This project incorporates cross-sectional and longitudinal in vivo neuroimaging data from the NAPLS2 cohort with publicly available human postmortem brain transcriptome data to test whether morphometric similarity networks and cognitive impairments are differentially affected in CHR youth that develop psychosis, whether these cortical patterns are linked to behavioral measures of WM, and whether affected frontotemporal regions have a unique pattern of glutamate/GABA transcript enrichment affected by SZ risk genes. If these hypotheses are confirmed, the project will provide evidence that cortical alterations are detectable prior to overt illness onset and associated with behavioral and molecular measures of cognitive dysfunction. To attain these research aims, I seek formal training in imaging genomics and longitudinal analysis methods, which is possible through structured coursework, mentoring from a team of distinguished scientists, and UCLA’s outstanding infrastructure for genomics, neuroimaging, and psychosis research. The primary mentor (Dr. Bearden) has internationally recognized expertise in psychosis and prospective longitudinal studies of related neurocognitive and neuroimaging phenotypes, with extensive experience as a successful research mentor. The core co-mentors have complementary expertise in bioinformatics and functional genomics (Dr. Gandal) and statistical genetics methods (Dr. Pasaniuc) critical for this proposal. My collaborator (Dr. Raznahan) has renowned expertise in developmental neuroimaging. A key consultant (Dr. Freimer) will allow for shared bioinformatics resources and core facilities to guide analyses in large-scale functional and developmental genomics approaches, and will provide focused training in lab leadership and career development. This K proposal will provide me with the in-depth training in research methodology and career support necessary for a successful transition to independence. This proposal aligns with the NIMH strategic objectives to define brain mechanisms underlying complex behaviors and to study mental illness trajectories across the lifespan.