Precision Medicine Approach: Using genomic information to guide TBI treatment

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。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仔细研究可以揭示 MTBI发病机制的分子决定因素的线索，包括疾病易感性。中概述的研究 该奖项旨在利用细胞中的基因组分析作为工具，为脑损伤病理提供线索和指导 治疗靶点的发现。我们发现，大脑中的甲状腺激素转运蛋白受体是一种 治疗干预的潜在目标。因此，该项目的一个重要目标是调查 甲状腺激素作为治疗剂的潜力。我们假设要检查甲状腺是否可能 激素T4治疗可以激活控制大脑回路功能的基因调节机制 对于高阶信息的处理很重要的区域。附录中涉及的研究(未包括在内 在父母赠款中)旨在补充关于T4治疗的行动的信息，以减少 颅脑损伤的病理学。由于T4新陈代谢的很大一部分发生在体内，我们将决定如何发挥作用 外周甲状腺激素的变化可以调节与脑出血相关的区域的中枢机制 认知功能，如海马体和下丘脑。事实上，T4在肝脏中代谢之前 到达脑和脑外伤的外周病理可能有助于调节脑病理。Dr。 梅尔卡多将进行研究，以确定T4在外周的新陈代谢如何影响 脑外伤的发病机制，按家长的范围给予资助。鉴于大脑的很大一部分 脂类在肝脏中代谢，我们将评估肝脂可以作为外周运输工具的可能性 脑损伤对脑功能和行为的影响。梅尔卡多博士将接受一系列新概念的培训 TBI领域的技术。此外，梅尔卡多博士将在以下网址与精英神经科学界接触 加州大学洛杉矶分校将参加为年轻调查人员提供的有组织的培训计划，在通往独立调查人员的道路上 学术生涯。

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.