The Genomics of Highly Treatment Resistant Schizophrenia

高度耐药性精神分裂症的基因组学

• 批准号: 9328158
• 负责人: Martilias Stephen Farrell
• 金额: $ 14.18万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-08 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9328158
• 关键词: Algorithms; Ambulatory Care Facilities; Animal Model; Award; Bioinformatics; Blood specimen; CLIA certified; Caring; Catalogs; Clinical; Clinical Medicine; Consent; Counseling; DNA Microarray Chip; DNA Sequence Alteration; Data; Data Set; Development; Diagnosis; Diagnostic; Disease; Drug Kinetics; Environment; Ethical Issues; Ethics; Etiology; Exposure to; Foundations; Funding; Future; Genes; Genetic; Genetic Research; Genetic Variation; Genetic screening method; Genome; Genomics; Genotype; Goals; Hepatolenticular Degeneration; Hereditary Disease; Heterogeneity; Immersion Investigative Technique; Individual; Inherited; Inpatients; Investigation; K-Series Research Career Programs; Laboratories; Laboratory Organism; Laboratory Research; Lead; Long QT Syndrome; Medical; Medical Genetics; Mendelian disorder; Mentorship; Modification; Mutation; Pathogenicity; Patients; Pennsylvania; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Pharmacological Treatment; Pharmacotherapy; Phenotype; Physicians; Process; Psychiatric Hospitals; Quality Control; Reporting; Research; Research Project Grants; Resistance; Risk; SNP array; Sampling; Schizophrenia; Symptoms; System; Testing; Therapeutic; Time; Training; Training Programs; Translating; Validation; Variant; Work; cancer risk; career; clinically actionable; clinically relevant; design; drug development; drug discovery; effective therapy; exome sequencing; genetic association; genetic variant; genome wide association study; genome-wide; genomic data; human genomics; insertion/deletion mutation; insight; legal implication; neuropsychopharmacology; new therapeutic target; novel; novel therapeutics; psychogenetics; rare variant; research and development; skills; social implication; therapeutic development; training opportunity; treatment strategy; ward

PROJECT SUMMARY / ABSTRACT My long term goal is to lead an independent research laboratory that translates psychiatric genetics findings into the development of novel therapeutics. My previous training in neuropsychopharmacology brought me to the forefront of contemporary psychiatric drug discovery efforts where I realized that novel therapeutic development is needed. Psychiatric genetics has the potential to uncover novel drug targets and treatment strategies. In order to effectively translate genetic findings to therapeutic drug development, I need the ability to analyze and interpret genetic findings in order to prioritize research and development efforts. My immediate career goal is to obtain the skill set necessary to use genomics data to advance psychotherapeutic development. The proposed 4-year career development award will provide an immersive training opportunity in psychiatric genetics that will enable me to design, execute, analyze, and interpret psychiatric genetic research. The proposed research project investigates the genomics of schizophrenia (SCZ) in a sample of highly treatment resistant subjects. These individuals are actively treated, adherent to prescribed medications, reside in a protected environment, do not abuse drugs, and yet many have been severely psychotic for years. The primary goal is to screen a subject’s genome for rare variation that can cause a clinical presentation initially indistinguishable from SCZ. We hypothesize that highly treatment resistant SCZ subjects have rare genetic mutations of strong effect, such as a Mendelian disease. Analysis of a large and notably severe SCZ sample will provide a rigorous test of this hypothesis. Positive findings could dramatically alter the clinical impact of SCZ genomics due to the availability of effective treatments for some disorders. First, we will establish our sample by obtaining consent, then phenotyping and collecting blood samples of patients. Second, we will perform high-throughput genotyping of these samples using whole exome sequencing and DNA microarrays. Third, we will screen these genomic data for rare variants of strong effect relating to their primary diagnosis and their pharmacological treatment. We will also look for and report any secondary findings. Prior to returning our findings to the medical team, the results will be verified by a CLIA-certified laboratory. Finally, we will identify rare variation for future studies (R01) and analyze the data for variation associated with highly treatment-resistant SCZ. In addition to the scientific and therapeutic benefits inherent in this work, this project provides an immersive training program in human genomics studies that aligns with my career goals. In addition to the training provided by the proposed research, I will also undertake an extensive training plan involving mentorship by leaders in the field of statistical genetics, bioinformatics, and the ethical, legal and social implications of medical genetics. Due to my strong background in neuropsychopharmacology, I will be able to use the skills acquired in the proposed project to launch into an independent research career investigating the therapeutic potential of psychiatric genomics findings. Furthermore, this project will provide a wealth of preliminary data for a subsequent R01 which will be prepared and submitted during year 4 of this training plan.

项目总结/摘要 我的长期目标是领导一个独立的研究实验室，将精神病遗传学的发现转化为 投入到新疗法的开发中我以前在神经精神药理学方面的训练使我 当代精神药物发现的最前沿，我意识到， 需要发展。精神病学遗传学有可能发现新的药物靶点和治疗方法 战略布局为了有效地将基因发现转化为治疗药物开发，我需要有能力 分析和解释基因发现，以优先考虑研究和开发工作。我的直系 职业目标是获得必要的技能，使用基因组学数据，以促进心理治疗 发展拟议的4年职业发展奖将提供身临其境的培训机会， 精神病学遗传学，这将使我能够设计，执行，分析和解释精神病学遗传研究。 拟议的研究项目调查精神分裂症（SCZ）的基因组学在一个高度 耐药受试者。这些人积极治疗，坚持处方药，居住在 在受保护的环境中，不滥用药物，但许多人多年来一直患有严重的精神病。的 主要目标是筛选受试者的基因组中可能导致最初临床表现的罕见变异 与SCZ没有区别。我们假设高度耐药的SCZ受试者具有罕见的遗传性， 突变的强烈影响，如孟德尔疾病。一个大而严重的SCZ样品的分析 将为这一假设提供严格的检验积极的发现可能会极大地改变 SCZ基因组学由于一些疾病的有效治疗的可用性。首先，我们将建立我们的 通过获得患者同意，然后对患者进行表型分析和采集血液样本。二是 使用全外显子组测序和DNA微阵列对这些样本进行高通量基因分型。 第三，我们将筛选这些基因组数据，以寻找与其初步诊断相关的具有强效应的罕见变异。 和他们的药物治疗。我们还将寻找并报告任何次要发现。返回之前 我们的调查结果向医疗小组，结果将由CLIA认证的实验室验证。最后我们将 确定未来研究的罕见变异（R 01），并分析与高度相关的变异数据 难治性SCZ除了这项工作所固有的科学和治疗益处外， 提供了一个沉浸式的人类基因组学研究培训计划，与我的职业目标相一致。在 除了拟议的研究所提供的培训外，我还将承担一项广泛的培训计划 包括统计遗传学，生物信息学和伦理，法律的和 医学遗传学的社会意义由于我在神经精神药理学方面的强大背景，我将 能够利用在拟议项目中获得的技能，开展独立的研究生涯 研究精神病基因组学发现的治疗潜力。此外，该项目将提供一个 随后R 01的大量初步数据将在本报告第4年编制并提交 培训计划。