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.

摘要 在美国，脑震荡或轻/中度颅脑损伤(MTBI)占脑损伤的绝大多数， 损害神经功能和认知能力，可持续数年。最初存活下来的神经元 侮辱表明功能下降，而mTBI最耐人寻味的方面之一是许多患者变得 容易受到继发性损伤或神经功能障碍的影响，潜在的指示隐藏在变化中 基因程序。缺乏关于脑损伤如何改变控制发病机制的基因调控程序的信息 阻碍了指导脑损伤治疗的战略取得重大进展。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 在程序中的基因可能是病理的致病因素，并可以揭示治疗的靶点，可以 支持精准医疗行动。我们最近实现了使用单细胞基因组分析来 阐明脑外伤对细胞类型、基因、途径和细胞间相互作用的影响，有助于了解 治疗的新靶点。我们的单细胞基因组分析结果表明，细胞新陈代谢是导致 MTBI在细胞水平的发病机制，并帮助我们优先考虑甲状腺激素(重要的代谢 调节剂)作为一种潜在的治疗剂。潜在的假设是用甲状腺激素治疗 T4可以激活基因调节机制，控制大脑重要区域的电路功能 高阶信息的处理。利用夏阳博士在基因组学和系统学方面的专业知识 生物学和脑损伤的费尔南多·戈麦斯-皮尼拉博士，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形成回路的细胞中基因表达的变化 正在处理。我们项目的一个独特方面是实施高度复杂的基因组程序来 了解神经修复和可塑性领域尚未解决的问题，并监测治疗的效果， 运用精准医学的基本概念。星形胶质细胞为神经元提供能量，它们扮演着至关重要的角色 在甲状腺激素从血液进入神经细胞的过程中起作用，根据我们的初步数据， 星形胶质细胞对创伤性脑损伤非常敏感。我们将调节星形胶质细胞的活动，以探讨星形胶质细胞在 脑外伤后的回路重组及其对甲状腺激素的影响。我们的研究有望开启新的 基于基因调控的细胞特定功能方面减轻mTBI病理的途径，这也是 这是精准医疗倡议的主要前提。