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: 10328921
• 负责人: Fernando Gomez-Pinilla
• 金额: $ 56.95万
• 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/10328921
• 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; Neuronal Plasticity; 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; neural repair; new therapeutic target; precision medicine; programs; 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 脑震荡损伤或轻度/中度TBI（MTBI）占美国大部分脑损伤的绝大多数 损害了可以持续多年的神经元功能和认知能力。生存初始的神经元 侮辱显示功能下降，MTBI最吸引人的方面之一是许多患者成为 容易受到继发性损伤或神经系统疾病的影响，而这些指令隐藏在改变中 基因程序。缺乏信息，TBI如何改变控制发病机理的基因调节程序 排除了指导TBI治疗剂的策略的重大进展。传统医学依靠 症状和表型的表现而不是病理的病因。相反，更改 在基因计划中，可能是病理学的致病因素 支持精密医学计划。我们最近实施了单细胞基因组分析的使用 阐明TBI对细胞类型，基因，途径和细胞 - 细胞相互作用的影响，可以帮助信息 治疗的新目标。我们来自单细胞基因组分析的结果表明细胞代谢是 MTBI在细胞水平上的发病机理，并帮助我们优先考虑甲状腺激素（重要代谢 调节剂）作为潜在的治疗剂。潜在的假设是用甲状腺激素治疗 T4可以激活控制大脑区域电路功能的基因调节机制，对 处理高阶信息。利用基因组学和系统的杨杨博士的专业知识 生物学和TBI中的Fernando Gomez-Pinilla博士，我们将利用最先进的平行单细胞测序 （Drop-seq）评估与认知相关的大脑区域形成电路中基因表达的变化 加工。我们项目的一个独特方面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中未解决的问题，并监测治疗的功效， 使用精密医学的基本概念。星形胶质细胞供应神经元使用的能量，它们发挥着重要的作用 从血液中掺入甲状腺激素到神经元细胞中的作用，并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活动以探测星形胶质细胞的作用 TBI和甲状腺激素的影响后的电路重组。我们的研究有望开放新的 基于基因调节的细胞特异性功能方面减轻MTBI病理的途径，这也是 精密医学计划的主要前提。