Precision Medicine Approach: Using genomic information to guide TBI treatment

精准医学方法：利用基因组信息指导 TBI 治疗

• 批准号: 10084332
• 负责人: Fernando Gomez-Pinilla
• 金额: $ 56.81万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084332
• 关键词: Acute; Affect; Astrocytes; Behavior; Behavioral; Bioenergetics; Biological; Biological Assay; Blood; Blood Circulation; Brain; Brain Concussion; Brain Injuries; Brain region; Cell Communication; Cells; Cellular Metabolic Process; Cognitive; Complement; Data; Defect; Development; Diagnostic; Energy Supply; Gene Expression; Gene Expression Regulation; Gene Mutation; Genes; Genomics; Hippocampus (Brain); In Situ Hybridization; Individual; Inflammation; Injury; Instruction; Intervention; Metabolic; Metabolic dysfunction; Metabolism; Molecular; Monitor; Neurons; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Performance; Phase; Phenotype; Play; Precision Medicine Initiative; Procedures; RNA; Regulator Genes; Role; Secondary to; Symptoms; Systems Biology; TBI treatment; Testing; Therapeutic; Therapeutic Agents; Thyroid Hormones; Thyroxine; Time; Traditional Medicine; Traumatic Brain Injury; Treatment Efficacy; Yang; base; brain cell; cell type; cognitive ability; dosage; droplet sequencing; frontal lobe; functional decline; gene function; metabolic depression; myelination; nervous system disorder; neural circuit; new therapeutic target; precision medicine; programs; relating to nervous system; repaired; response; restoration; single cell analysis; single cell sequencing; targeted treatment; therapeutic target; transcriptomics; treatment strategy

Abstract Concussive injury or mild/moderate TBI (mTBI) accounts for a large majority of the brain injuries in USA and compromises neuronal function and cognitive abilities that can last for years. Neurons that survive the initial insult show a decline in function, and one of the most intriguing aspects of mTBI is that many patients become vulnerable to secondary injury or neurological disorders, which underlying instructions are hiding in alterations of gene programs. The lack of information how TBI alters gene regulatory programs that govern pathogenesis has precluded major advances in strategies to guide TBI therapeutics. Traditional medicine relies on manifestations of symptoms and phenotypes rather than causative factors of the pathology. Instead, alterations in the program of genes are likely causative factors of the pathology and can reveal therapeutic targets that can support precision medicine initiatives. We have recently implemented the use of single-cell genomic analysis to elucidate the impact of TBI on cell types, genes, pathways, and cell-cell interactions that can help inform on novel targets for therapy. Our results from single-cell genomic analysis point to cell metabolism as a driver of mTBI pathogenesis at the cell level and has helped us to prioritize thyroid hormone (important metabolic modulator) as a potential therapeutic agent. The underlying hypothesis is that treatment with thyroid hormone T4 can activate gene regulatory mechanisms that control functionality of circuits in brain regions important for processing of higher order information. Leveraging the expertise of Dr. Xia Yang in genomics and systems biology, and Dr. Fernando Gomez-Pinilla in TBI, we will utilize state-of-the-art parallel single cell sequencing (drop-seq) to assess changes in gene expression in cells forming circuits in brain regions related to cognitive processing. A unique aspect of our project is the implementation of highly sophisticated genomic procedures to understand unsolved questions in the field of neural repair and plasticity and to monitor the efficacy of treatments, using basic concepts of precision medicine. Astrocytes supply energy used by neurons, and they play a crucial role in the incorporation of thyroid hormone from blood into neuronal cells, and according to our preliminary data, astrocytes are highly vulnerable to TBI. We will modulate astrocyte activities to probe the role of astrocytes on circuit reorganization after TBI and on the effects of thyroid hormone. Our studies have the promise to open new avenues to mitigate mTBI pathology based on cell-specific functional aspects of gene regulation, which is also a main premise for precision medicine initiatives.

抽象的 在美国和美国，脑损伤绝大多数是由脑震荡或轻度/中度 TBI (mTBI) 造成的 神经元功能和认知能力的损害可能会持续数年。最初存活下来的神经元 损伤表现出功能下降，mTBI 最有趣的方面之一是许多患者变得 容易受到二次伤害或神经系统疾病，这些潜在的指令隐藏在改变中 基因程序。缺乏 TBI 如何改变控制发病机制的基因调控程序的信息 阻碍了指导 TBI 治疗策略的重大进展。传统医学依赖于 症状和表型的表现，而不是病理的致病因素。相反，改变 基因程序中的基因可能是病理学的致病因素，并且可以揭示治疗靶标 支持精准医疗举措。我们最近利用单细胞基因组分析来 阐明 TBI 对细胞类型、基因、通路和细胞间相互作用的影响，有助于了解 新的治疗目标。我们的单细胞基因组分析结果表明细胞代谢是 mTBI 在细胞水平上的发病机制，帮助我们优先考虑甲状腺激素（重要的代谢 调节剂）作为潜在的治疗剂。基本假设是甲状腺激素治疗 T4 可以激活基因调节机制，控制大脑区域中重要的电路功能。 处理高阶信息。利用夏阳博士在基因组学和系统方面的专业知识 生物学和 TBI 领域的 Fernando Gomez-Pinilla 博士，我们将利用最先进的并行单细胞测序 （drop-seq）评估与认知相关的大脑区域中形成回路的细胞的基因表达变化 加工。我们项目的一个独特之处是实施高度复杂的基因组程序 了解神经修复和可塑性领域未解决的问题并监测治疗效果， 使用精准医学的基本概念。星形胶质细胞提供神经元使用的能量，它们起着至关重要的作用 甲状腺激素从血液中掺入神经元细胞中的作用，根据我们的初步数据， 星形胶质细胞极易受到 TBI 的影响。我们将调节星形胶质细胞的活动来探讨星形胶质细胞在 TBI 后的回路重组以及甲状腺激素的影响。我们的研究有望开辟新的领域 基于基因调控的细胞特异性功能方面减轻 mTBI 病理的途径，这也是 精准医疗计划的一个主要前提。