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: 10303991
• 负责人: Fernando Gomez-Pinilla
• 金额: $ 10.62万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303991
• 关键词: Area; Award; Behavior; Brain; Brain Concussion; Brain Injuries; Brain Pathology; Brain region; Cell physiology; Cells; Communities; Complement; Disease; Exposure to; Genomics; Goals; Hippocampus (Brain); Hypothalamic structure; Injury; Lipids; Liver; Metabolism; Molecular; Neurons; Neurosciences; Parents; Pathogenesis; Pathology; Peripheral; Predisposition; Regulator Genes; Research; Research Personnel; TBI treatment; Techniques; Therapeutic Agents; Therapeutic Intervention; Thyroid Hormone Receptor; Thyroid Hormones; Thyroxine; Training; Training Programs; career; cognitive ability; cognitive function; guided inquiry; parent grant; precision medicine; programs; targeted treatment; therapeutic target; tool

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. The main premise of the parent grant is that gene regulatory programs determine cellular functions such that scrutiny of large-scale genomic changes can reveal clues to the molecular determinants of mTBI pathogenesis, including disease predisposition. Studies outlined in the award are directed to use genomic analysis in cells as a tool to provide leads to the TBI pathology and guide the discovery of therapeutic targets. We found that the receptor for thyroid hormone transporter in the brain is a potential target for therapeutic interventions. Therefore, an important goal of the project is to investigate the potential of thyroid hormone to be used as a therapeutic agent. We posit to examine the possibility that thyroid hormone T4 treatment can activate gene regulatory mechanisms that control functionality of circuits in brain regions important for processing of higher order information. Studies involved in the supplement (not included in the parent grant) are directed to complement information about the action of T4 treatment to reduce the pathology of TBI. Since a large aspect of T4 metabolism occurs in the body, we will determine how the action of thyroid hormone in the periphery can modulate central mechanisms in areas associated with processing of cognitive function such as the hippocampus and hypothalamus. Indeed, T4 is metabolized in the liver before reaching the brain and the peripheral pathology of TBI can contribute to modulate the brain pathology. Dr. Mercado will conduct research directed to determine how the metabolism of T4 in the periphery influences the TBI pathogenesis in the brain, according to the scope of the parent grant. Given that a large portion of brain lipids are metabolized in liver, we will assess the possibility that liver lipids can be a vehicle for the periphery to influence TBI on brain function and behavior. Dr. Mercado will be trained in a myriad of new concepts and techniques in the field of TBI. In addition, Dr. Mercado will be exposed to the elite neuroscience community at UCLA and will participate in organized training programs for young investigators on the path to an independent academic career.

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 损害神经元功能和认知能力。父母资助的主要前提是基因 调控程序决定细胞功能，因此对大规模基因组变化的审查可以揭示 mTBI 发病机制的分子决定因素（包括疾病易感性）的线索。研究概述于 该奖项旨在利用细胞基因组分析作为工具，为 TBI 病理学提供线索并提供指导 治疗靶点的发现。我们发现大脑中甲状腺激素转运蛋白的受体是 治疗干预的潜在目标。因此，该项目的一个重要目标是调查 甲状腺激素作为治疗剂的潜力。我们假设检查甲状腺的可能性 激素 T4 治疗可以激活控制大脑回路功能的基因调节机制 对于处理高阶信息很重要的区域。补充中涉及的研究（不包括 在母基金中）旨在补充有关 T4 治疗作用的信息，以减少 TBI 的病理学。由于 T4 代谢的很大一部分发生在体内，我们将确定该作用如何 外周的甲状腺激素可以调节与处理相关区域的中枢机制 认知功能，例如海马体和下丘脑。事实上，T4 在肝脏中代谢之前 TBI 到达大脑和外周病理学有助于调节大脑病理学。博士。 Mercado 将开展研究，以确定外周 T4 的代谢如何影响 TBI发病于脑，依母授范围。鉴于大脑的很大一部分 脂质在肝脏中代谢，我们将评估肝脏脂质可以作为外周脂质的载体的可能性 影响 TBI 对大脑功能和行为的影响。梅尔卡多博士将接受无数新概念的培训 TBI 领域的技术。此外，Mercado 博士还将接触到神经科学界的精英人士 加州大学洛杉矶分校并将参加为年轻研究者走上独立之路而组织的培训项目 学术生涯。