BCM Center for Precision Medicine Models

BCM 精准医学模型中心

• 批准号: 10471388
• 负责人: Lindsay C Burrage
• 金额: $ 198.95万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471388
• 关键词: Affect; Animal Model; Back; Bioinformatics; Caring; Clinical; Clinical Research; Clinical Trials; Collaborations; Communities; DNA lesion; Databases; Development; Diagnosis; Diagnostic; Disease; Disease model; Drosophila melanogaster; Genes; Genetic Diseases; Genome; Genomics; Goals; House mice; Human Genetics; Human Genome; Individual; Infrastructure; International; Leadership; Medical Genetics; Medicine; Mendelian disorder; Modeling; Modification; Molecular; Molecular Genetics; Mus; Patient Care; Patients; Phenotype; Production; Provider; Rare Diseases; Reporting; Research Personnel; Resources; Structure; Study models; Techniques; Technology; Translating; Translations; Variant; Vision; body system; clinical care; clinical diagnostics; clinically significant; college; design; exome sequencing; fly; gene discovery; genetic disorder diagnosis; genome sequencing; metabolomics; multidisciplinary; nonhuman primate; personalized approach; personalized medicine; precision medicine; preclinical study; programs; recruit; therapeutic evaluation; tool; transcriptome sequencing; translational impact; translational study; variant of unknown significance; whole genome

ABSTRACT The introduction of clinical exome sequencing, whole genome sequencing, RNA sequencing, and metabolomics has transformed our ability to diagnose patients with suspected genetic disease. With the introduction of these technologies, a potential molecular DNA lesion can be identified in at least 25-30% of patients with a suspected genetic diagnosis. These technologies have also led to the discovery of hundreds of new disease genes and to phenotypic expansion within known genetic diagnoses. This continued discovery of new disease genes leads to structure, function and mechanistic discoveries that assist personalized approaches for management and therapy. However, up to 70% of patients with suspected genetic disease remain undiagnosed likely because their disease-causing variant(s) has yet to be discovered or the clinical significance of identified variants remains unclear. Precision models produced using various genome modification techniques in Drosophila melanogaster (fly) and Mus musculus (mouse) are important tools aiding in the interpretation of these variants of uncertain clinical significance and are critical for testing therapeutic paradigms. We will leverage the expertise, infrastructures, and established collaborations between the rare, Mendelian disease clinical and gene discovery programs; fly, mouse, and nonhuman primate animal modeling programs; and database infrastructure programs within the Department of Molecular and Human Genetics (DMHG) at the Baylor College of Medicine (BCM) to establish the BCM Center for Precision Medicine Modeling (BCPMM). The vision of our Center is to support local, national, and international programs and individual researchers in the development of precision models that will end the diagnostic odyssey of patients with undiagnosed, rare, and Mendelian diseases and serve as resources for pre-clinical studies investigating personalized medicine approaches to their care. We will achieve these goals by pursuing the following aims: (1) leverage existing multidisciplinary expertise within BCM to design, generate, and identify precision animal models for studies that answer clinical questions with impact on patient care; (2) conduct demonstration projects that showcase the Center’s capacity to model undiagnosed and rare diseases and to translate model organism findings back to patient care; (3) Engage human genome discovery programs, clinicians, and researchers to recruit disease-associated variant nominations for precision model studies within the Center; (4) Perform bidirectional translation of findings from precision animal models and from patient clinical studies for integration into clinical diagnostics, clinical care, or clinical trials; (5) Implement bioinformatics platforms that optimize Center disease modeling and organizational activities. Although our initial focus will build on our expertise in undiagnosed, rare, and Mendelian diseases, our long-term goal is to broaden our scope by establishing collaborations with investigators and programs focused on multigenic and common disease.

抽象的 引入临床外显子组测序，整个基因组测序，RNA测序和代谢组学 已经改变了我们诊断疑似遗传疾病患者的能力。随着这些的引入 在至少25-30％的患者中，可以鉴定出潜在的分子DNA病变的技术。 遗传诊断。这些技术还导致发现了数百种新疾病基因，并 已知遗传诊断内的表型扩张。这种继续发现新疾病基因导致 结构，功能和机械发现，可帮助管理的个性化方法和 治疗。然而，多达70％的怀疑遗传疾病患者仍然可能无法诊断 它们的引起疾病的变体尚未发现或确定变体的临床意义 不清楚。使用果蝇果蝇中的各种基因组修饰技术生成的精确模型 （苍蝇）和mus musculus（小鼠）是协助解释这些不确定变体的重要工具 临床意义，对于测试治疗范例至关重要。我们将利用专业知识， 基础设施，并在罕见的孟德尔病临床和基因发现之间建立了合作 程序；苍蝇，老鼠和非人类灵长类动物建模计划；和数据库基础架构程序 在贝勒医学院（BCM）的分子和人类遗传学系（DMHG）内 建立BCM精密医学建模中心（BCPMM）。我们中心的愿景是支持 当地，国家和国际计划以及精确模型开发的个人研究人员 这将结束未经诊断，罕见和孟德尔疾病的患者的诊断漫游，并用作 临床前研究的资源研究了个性化医学方法的护理方法。我们将 通过追求以下目标来实现这些目标：（1）利用BCM中现有的多学科专业知识 设计，生成和确定针对影响临床问题的研究精确动物模型 在患者护理上； （2）进行演示项目，以展示中心的未诊断能力 和罕见疾病，将模型生物发现转化回患者护理； （3）参与人类基因组 发现计划，临床医生和研究人员，以招募与疾病相关的变体提名 中心内的模型研究； （4）从精密动物模型中进行发现的双向翻译 以及患者临床研究以整合到临床诊断，临床护理或临床试验中； （5） 实施优化中心疾病建模和组织活动的生物信息学平台。 尽管我们最初的重点将基于我们在未诊断，罕见和孟德尔疾病方面的专业知识，但我们的长期 目标是通过与关注的调查人员和计划建立合作来扩大我们的范围 多基因和普通疾病。