Preclinical/Co-Clinical Section

临床前/临床联合部分

基本信息

批准号：
10259806
负责人：
Lindsay C Burrage
金额：
$ 25.48万
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/10259806
关键词：
Adult Animal Model Back Childhood Clinical Clinical Research Clinical Trials Collaborations Communities DNA Sequencing Facility DNA lesion Data Databases Diagnosis Diagnostic Diet Disease Drosophila melanogaster Drug Screening Evaluation Family Genes Genetic Genetic Counseling Genetic Diseases Genome Genomic medicine Genomics Genotype House mice Individual Infrastructure Institutes Laboratories Laboratory mice Medical Records Modeling Modification Molecular Mus Nutritional Participant Patients Phenotype Play Pre-Clinical Model Preventive Medicine Provider Research Research Infrastructure Research Personnel Resources Role Scientist Site Structure Technology Therapeutic Therapeutic Agents Time Translating Translational Research Translations Variant Vitamins biomarker discovery clinical care clinical diagnostics clinical research site clinically significant cost drug repurposing empowered exome sequencing fly gene discovery genetic disorder diagnosis genome sequencing human disease human genome sequencing human model mRNA sequencing metabolomics network models new technology nonhuman primate novel therapeutics personalized approach personalized medicine pre-clinical precision medicine prenatal programs screening success tool translational impact whole genome

项目摘要

ABSTRACT The introduction of clinical exome sequencing and whole genome sequencing has transformed our ability to diagnose patients with suspected genetic disease. Clinical exome sequencing identifies a potential molecular DNA lesion in at least 25-30% of patients with a suspected genetic diagnosis. New technologies such as genome sequencing, mRNA sequencing, and metabolomics profiling are continuing to increase this diagnostic rate. In addition, the introduction of these technologies has 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 point to personalized approaches for management and therapy. Moreover, a precise genetic diagnosis ends the costly diagnostic odyssey, facilitates personalized preventive medicine for long-term complications of the diagnosis, enables appropriate anticipatory guidance, and facilitates genetic counseling for families. 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 because the clinical significance of variants identified in genomic studies remains unclear. Collaborations between clinician scientists and model organism researchers have played a fundamental role in facilitating this revolution in genomic medicine. Model organisms, such as the fruity fly and laboratory mouse, are important tools for aiding in the interpretation of variants identified in sequencing data. In some cases, model organisms have provided key data supporting the association of a phenotype with a new disease gene. Beyond modeling the genotype and phenotype, studies in model organisms, such as fly, mouse, and non-human primates, may inform therapeutic management of patients with genetic disorders. In addition, these model organisms provide key resources for biomarker discovery, drug screens, and evaluation of genotype-specific therapeutic strategies. Our previous success in precision modeling of human disease at BCM is due to strong collaborative efforts between local clinicians, genome scientists, and model organism scientists that is afforded by the integration of basic, translational, clinical, and diagnostic activities housed within the DMHG at BCM. This integration has established a flow of clinical and genomic information from prenatal, pediatric and adult genetics patients and study participants to laboratory geneticists at Baylor Genetics and various gene discovery programs. In so doing, we have established and modeled the clinical, preclinical, and model organism workflow that we are now extending to mammalian species. Our Preclinical/Co-Clinical section will leverage this existing infrastructure and expertise and extend its use to the wider community through the following aims: 1) Coordinate and review variant nominations, 2) Formulate clinical questions requiring precision modeling, and 3) Translate clinical significance of precision models.

抽象的临床外显子组测序和整个基因组测序的引入使我们的能力改变了诊断患有遗传疾病的患者。临床外显子组测序鉴定了潜在的分子怀疑遗传诊断的患者中，至少25-30％的DNA病变。基因组等新技术测序，mRNA测序和代谢组学分析正在继续提高此诊断率。在此外，这些技术的引入导致发现了数百种新疾病基因和在已知遗传诊断中进行表型扩张。这种持续发现新疾病基因引导结构，功能和机理发现，指出了个性化的管理方法治疗。此外，精确的遗传诊断结束了昂贵的诊断性奥德赛，促进了个性化预防医学对于诊断的长期并发症，可以实现适当的预期指导，并促进家庭的遗传咨询。但是，多达70％的疑似遗传疾病患者仍然无法诊断，可能是因为尚未发现其引起疾病的变体或基因组研究中发现的变体的临床意义尚不清楚。临床医生之间的合作科学家和模型生物研究人员在促进这场革命的基本作用基因组医学。模型生物（例如果味苍蝇和实验室鼠标）是协助的重要工具在测序数据中识别的变体的解释中。在某些情况下，模型生物提供了支持表型与新疾病基因的关联的关键数据。除了建模基因型和表型，在模型生物（例如蝇，小鼠和非人类灵长类动物）中的研究可能会告知遗传疾病患者的治疗管理。此外，这些模型生物提供了关键生物标志物发现，药物筛查的资源和基因型特异性治疗策略的评估。我们以前在BCM的人类疾病精确建模取得了成功，这是由于强大的协作努力在当地临床医生，基因组科学家和模型生物科学家之间，这是由一体化所提供的在BCM的DMHG内包含的基本，翻译，临床和诊断活动。这种整合具有从产前，儿科和成人遗传学患者以及研究贝勒遗传学和各种基因发现计划的实验室遗传学家的参与者。这样做，我们已经建立并建立了我们现在正在建立的临床，临床前和模型的生物工作流程扩展到哺乳动物。我们的临床前/共同链接部分将利用这一现有基础架构和专业知识，并通过以下目的将其使用扩展到更广泛的社区：1）协调和审查变体提名，2）提出需要精确建模的临床问题，3）翻译临床精确模型的重要性。