Imaging transcriptomics across developmental stages of early psychotic illness

早期精神病发展阶段的转录组学成像

• 批准号: 10664783
• 负责人: GIL D HOFTMAN
• 金额: $ 19.66万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664783
• 关键词: Adolescence; Adolescent; Adult; Affect; Anatomy; Anterior; Area; Atlases; Autopsy; Behavior; Behavioral; Bioinformatics; Bioinformatics Shared Resource; Brain; Cessation of life; Chronic; Chronic Schizophrenia; Clinical; Cognition; Cognition Disorders; Cognitive; Complex; Core Facility; Data; Data Set; Development; Dimensions; Early Intervention; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomic approach; Genomics; Glutamates; Human; Image; Impaired cognition; Impairment; Individual; Infrastructure; International; Intervention; Link; Longevity; Longitudinal Studies; Longitudinal cohort; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Memory impairment; Mental disorders; Mentors; Methods; Molecular; Molecular Genetics; National Institute of Mental Health; Neocortex; Neurocognitive; Neurons; Neurosciences; Onset of illness; Outcome; Parvalbumins; Pathway Analysis; Pattern; Performance; Phenotype; Physicians; Population; Prevention; Primates; Process; Psychoses; Psychotic Disorders; Research; Research Methodology; Research Personnel; Resources; Schizophrenia; Scientist; Short-Term Memory; Standardization; Structure; Synapses; Testing; Thinness; Time; Tissues; Training; Training Support; Transcript; Work; Youth; behavior measurement; career; career development; cell type; clinical high risk for psychosis; cognitive function; cohort; disability; experience; first episode psychosis; follow-up; functional genomics; gamma-Aminobutyric Acid; high risk; hippocampal pyramidal neuron; improved; in vivo; indexing; leadership development; longitudinal analysis; longitudinal, prospective study; neocortical; nervous system development; neural circuit; neurodevelopment; neuroimaging; novel; premature; prospective; psychosis risk; risk variant; schizophrenia risk; transcriptome; transcriptomics

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.

项目概要/摘要 作为神经发育研究领域的医师科学家，具有深厚的分子背景 神经科学，我寻求对新颖分析培训的指导支持，以整合神经影像学和分子学 在我成为一名独立研究者的道路上，我提出了一个综合性的研究。 项目重点关注精神病临床高风险 (CHR) 青少年的前瞻性纵向队列 (NAPLS2) 利用神经影像分析和高通量、公开的全脑转录组学方面的进步 先前的研究表明，研究精神分裂症（SZ）风险的神经发育机制。 认知功能障碍是 SZ 的核心特征，工作记忆 (WM) 通常会在整个过程中逐渐成熟 青春期，明显的临床精神病发作最常见，WM 部分取决于广泛的 然而，分布式皮质谷氨酸和 GABA 介导的神经回路。 SZ 的认知功能障碍是有限的，该项目结合了体内的横截面和纵向。 来自 NAPLS2 队列的神经影像数据以及公开的人类死后大脑转录组数据 测试 CHR 中形态相似性网络和认知障碍是否受到不同影响 患有精神病的青少年，这些皮质模式是否与 WM 的行为测量有关，以及 影响额颞区是否具有独特的谷氨酸/GABA 转录物富集模式 如果这些假设得到证实，该项目将提供皮质改变的证据。 在明显的疾病发作之前即可检测到，并与认知的行为和分子测量相关 功能障碍。 为了实现这些研究目标，我寻求影像基因组学和纵向分析方面的正式培训 方法，这可以通过结构化课程、杰出科学家团队的指导来实现， 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拥有出色的基础设施。 （比尔登博士）在精神病和前瞻性纵向研究方面拥有国际公认的专业知识 相关的神经认知和神经影像表型，具有丰富的成功研究经验 核心共同导师在生物信息学和功能基因组学方面拥有互补的专业知识（Dr. Gandal）和统计遗传学方法（Pasaniuc 博士）对于我的合作者（Raznahan 博士）至关重要。 一位关键顾问（Freimer 博士）在发育神经影像方面拥有著名的专业知识，将允许共享。 指导大规模功能和发育分析的生物信息学资源和核心设施 基因组学方法，并将提供实验室领导力和职业发展方面的重点培训。 提案将为我提供研究方法方面的深入培训和职业支持所需的 该提案符合 NIMH 定义大脑的战略目标。 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。