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.

摘要 在美国，脑震荡损伤或轻度/中度TBI（mTBI）占脑损伤的绝大多数， 损害神经元功能和认知能力。父母补助金的主要前提是基因 调控程序决定细胞功能，因此对大规模基因组变化的研究可以揭示 mTBI发病机制的分子决定因素的线索，包括疾病易感性。概述的研究 该奖项旨在利用细胞中的基因组分析作为工具，为TBI病理学提供线索， 治疗靶点的发现我们发现大脑中甲状腺激素转运体的受体是一种 治疗干预的潜在目标。因此，该项目的一个重要目标是调查 甲状腺激素用作治疗剂的潜力。我们要检查甲状腺 激素T4治疗可以激活控制大脑回路功能基因调节机制 对处理高阶信息重要的区域。补充材料中涉及的研究（不包括 在父母补助金）是针对补充信息的行动，T4治疗，以减少 TBI的病理学由于T4代谢的一个大的方面发生在体内，我们将确定如何行动， 甲状腺激素在外周可以调节中枢机制与处理相关的领域， 认知功能，如海马体和下丘脑。事实上，T4在肝脏中代谢之前 到达脑和TBI的外周病理可以有助于调节脑病理。博士 梅尔卡多将进行研究，以确定如何代谢的T4在周边影响， 脑外伤的发病机制，根据父母补助的范围。鉴于大脑的大部分 脂质在肝脏中代谢，我们将评估肝脏脂质作为外周代谢载体的可能性， TBI对脑功能和行为影响。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，梅尔卡多博士将接触到精英神经科学界在 加州大学洛杉矶分校，并将参加有组织的培训计划，为年轻的调查人员的道路上，一个独立的 学术生涯。