BCM Center for Precision Medicine Models

BCM 精准医学模型中心

基本信息

批准号：
10259804
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
项目类别：
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/10259804
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

项目摘要

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.

抽象的临床外显子组测序、全基因组测序、RNA测序和代谢组学的介绍随着这些的引入，改变了我们诊断疑似遗传病患者的能力。技术，至少 25-30% 的疑似患者存在潜在的分子 DNA 损伤这些技术还导致了数百种新疾病基因的发现。已知基因诊断中表型的扩展导致了新疾病基因的不断发现。结构、功能和机制的发现，有助于个性化的管理方法和然而，高达 70% 的疑似遗传病患者仍未得到诊断，可能是因为其致病变异尚未被发现，或者已识别变异的临床意义仍然存在尚不清楚，在果蝇中使用各种基因组修饰技术产生的精密模型。（苍蝇）和小家鼠（小鼠）是帮助解释这些不确定性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，并在罕见的孟德尔疾病临床和基因发现之间建立了合作程序；苍蝇、小鼠和非人类灵长类动物建模程序和数据库基础设施程序；贝勒医学院 (BCM) 分子与人类遗传学系 (DMHG) 建立 BCM 精准医学建模中心 (BCPMM) 我们中心的愿景是提供支持。精密模型开发中的地方、国家和国际项目以及个人研究人员这将结束未确诊、罕见和孟德尔疾病患者的诊断之旅，并作为我们将提供用于调查个性化医疗方法的临床前研究资源。通过追求以下目标来实现这些目标：(1) 利用 BCM 内现有的多学科专业知识设计、生成和识别用于研究的精密动物模型，以有效地回答临床问题 (2) 开展示范项目，展示中心对未确诊患者进行建模的能力和罕见疾病，并将模型生物的发现转化为患者护理（3）利用人类基因组；发现计划、大众和研究人员招募与疾病相关的变异提名以实现精确性中心内的模型研究；（4）对精密动物模型的研究结果进行双向转化以及整合到临床诊断、临床护理或临床试验中的患者临床研究 (5)；实施生物信息学平台，优化中心疾病建模和组织活动。尽管我们最初的重点将建立在我们在未确诊、罕见和孟德尔疾病方面的专业知识上，但我们的长期目标是目标是通过与研究人员和项目建立合作来扩大我们的范围多基因和常见疾病。