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.

项目摘要 /摘要 我的长期目标是领导一个独立的研究实验室，该实验室翻译精神遗传学发现 进入新疗法的发展。我以前在神经心理药理方面的培训使我进入 当代精神病药物发现工作的最前沿，我意识到这种新颖的疗法 需要开发。精神遗传学有可能发现新颖的药物靶标和治疗 策略。为了有效地将遗传发现转化为治疗药物的开发，我需要能够 分析和解释遗传发现，以优先考虑研发工作。我的直接 职业目标是获得使用基因组数据来推动心理治疗所需的技能集 发展。拟议的4年职业发展奖将为身临其境提供沉浸式培训机会 精神病遗传学将使我能够设计，执行，分析和解释精神病遗传学研究。 提出的研究项目研究了高度样本中精神分裂症（SCZ）的基因组学 耐药受试者。这些人受到积极治疗，遵守处方药，后方 在受保护的环境中，不要滥用药物，但许多人多年来一直处于严重的精神病状态。 主要目标是筛选受试者的基因组，以实现罕见变异，该变异最初可能导致临床表现 与SCZ无法区分。我们假设高度耐药的SCZ受试者具有罕见的遗传 强烈作用的突变，例如孟德尔病。分析大型且尤其是严重的SCZ样品 将对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基因组学因某些疾病有效治疗而导致。首先，我们将建立我们的 通过获得同意，然后表型和收集患者的血液样本。第二，我们会的 使用整个外显子组测序和DNA微阵列对这些样品进行高通量基因分型。 第三，我们将筛选这些基因组数据，以了解与其主要诊断有关的稀有效果的稀有变体 及其药理治疗。我们还将寻找并报告任何次要发现。返回之前 我们向医疗团队的发现，结果将由CLIA认证的实验室验证。最后，我们会的 确定未来研究的罕见变化（R01），并分析与高度相关的变异的数据 耐药性SCZ。除了这项工作固有的科学和治疗益处外，该项目 在人类基因组学研究中提供了一个沉浸式培训计划，该计划与我的职业目标保持一致。在 除了拟议的研究提供的培训外，我还将执行广泛的培训计划 涉及统计遗传学，生物信息学和道德，法律和法律和法律和法律的领导者的心态 医学遗传学的社会影响。由于我在神经心理学方面的强烈背景，我将 能够利用拟议项目中获得的技能来启动独立研究职业 研究精神基因组学发现的治疗潜力。此外，该项目将提供 随后的R01的大量初步数据，该数据将在此期间准备并提交 培训计划。