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 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 妥协神经元功能和认知能力。父母赠款的主要前提是基因 调节程序确定细胞功能，以便对大规模基因组变化的审查揭示 MTBI发病机理的分子决定因素的线索，包括疾病易感性。概述的研究 该奖项被指示使用细胞中的基因组分析作为提供TBI病理学并指导的工具 发现治疗靶标。我们发现脑在大脑中的甲状腺激素转运蛋白的受体是 治疗干预措施的潜在目标。因此，该项目的一个重要目标是调查 甲状腺激素的潜力用作治疗剂。我们认为甲状腺的可能性 激素T4处理可以激活控制大脑电路功能的基因调节机制 区域对于处理高阶信息很重要。补充剂涉及的研究（不包括 在父母的赠款中）指示补充有关T4治疗行动以减少的信息 TBI的病理学。由于T4代谢的大部分发生在体内，我们将确定动作如何 外围甲状腺激素的甲状腺激素可以调节与加工有关 认知功能，例如海马和下丘脑。确实，T4在肝脏之前已代谢 到达大脑和TBI的外周病理学可以有助于调节大脑病理。博士 Mercado将进行指导的研究，以确定T4在外围的代谢如何影响 根据父授予的范围，大脑中的TBI发病机理。鉴于很大一部分大脑 脂质是在肝脏中代谢的，我们将评估肝脂质可以成为外围的载体的可能性 影响TBI对脑功能和行为。 Mercado博士将接受无数新概念的培训， TBI领域的技术。此外，Mercado博士将接触到Elite神经科学社区 加州大学洛杉矶分校（UCLA），并将为年轻调查员参加有组织的培训计划 学术生涯。