Supplement for Ligand discovery for delineating cholesterol homeostasis in the brain

用于描述大脑胆固醇稳态的配体发现的补充

• 批准号: 10613677
• 负责人: Steven H Liang
• 金额: $ 34.93万
• 依托单位: EMORY UNIVERSITY
• 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613677
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Affect; Aging; Area; Behavioral; Biological; Biological Markers; Brain; Cholesterol; Cholesterol Homeostasis; Data; Dementia; Deterioration; Disease; Evaluation; Functional disorder; Goals; HIV; HIV Infections; HIV-1; Imaging Device; Immunohistochemistry; Impaired cognition; Impairment; Infection; Knowledge; Ligands; Modeling; Molecular; Monitor; N-Methylaspartate; Neurocognitive; Neuroimmune; Neuroimmune system; Neurologic; Neurons; Outcome; Pathogenesis; Pathway interactions; Patients; Phase; Physiological; Positron-Emission Tomography; Process; Proteins; Rattus; Research; Rodent Model; Science; Signal Transduction; Surrogate Markers; Synapses; System; Time; Tracer; Transgenic Organisms; United States; United States National Institutes of Health; Validation; Western Blotting; brain tissue; design; excitotoxicity; experimental study; in vivo; lipid disorder; longitudinal positron emission tomography; molecular imaging; motor symptom; neuroimaging; neuroinflammation; novel; novel diagnostics; pre-clinical; synaptic function; treatment strategy; uptake; young adult

Project Summary: HIV-1 is the causative agent of acquired immunodeficiency syndrome (AIDS), which is a multi-system disorder including the CNS. Neurological impairment affects approximately 60% of HIV-infected patients. HIV-1 enters the CNS at the early phase of infection, persists in that system for decades and induces multiple symptoms of motor, cognitive dysfunction and behavioral changes. Recently it has been estimated that nearly 30% of adults infected with HIV are affected. In the United States, HIV-1 infection is the most common cause of dementia in young adults. The more subtle forms of neurocognitive dysfunction however became more prevalent, leading to gradual, but ultimately significant functional deterioration of otherwise virologically controlled HIV+ patients. Among various factors, excitotoxic damage, neuroimmune dysfunction, lipid disorders and synaptic function are major factors in the HIV progression and aging process. Although all these remarkable discoveries have been made in the understanding of HIV-1 infection in the CNS at the molecular level via ex vivo (destructive) analysis, it cannot be directly applied to most brain tissues in vivo. Non-invasive PET neuroimaging approach can fill this void and provide direct and real-time correlation of aforementioned important signaling activity in the infected brain, facilitating novel HIV-1 neurotherapies. Therefore, we envision to directly monitor excitotoxicity (target: GluN2B-NMDA subtype), neuroinflammation (P2X7), cholesterol (CTP46A1) and synaptic (SV2A) function by PET as surrogate biomarkers in vivo in the brain of HIV-1 transgenic rat models. We speculate that longitudinal PET imaging of four distinct molecular imaging pathways will not only provide novel diagnostics to guide treatment strategies, but also study underlying mechanism of long-term HIV disease and aging, dysfunctional neuroimmune system as highlighted in the “Key NIH HIV Research Areas FY 2021-2025”.

项目概述：HIV-1是获得性免疫缺陷综合征（AIDS）的病原体， 包括CNS在内的多系统疾病。神经功能障碍影响约60%的艾滋病毒感染者 患者HIV-1在感染的早期阶段进入CNS，在该系统中持续数十年，并诱导 运动、认知功能障碍和行为改变的多种症状。最近据估计， 近30%的成年艾滋病毒感染者受到影响。在美国，HIV-1感染是最常见的 导致年轻人痴呆的原因然而，神经认知功能障碍的更微妙形式变得更加复杂。 流行，导致逐渐的，但最终显着的功能恶化，否则病毒控制 艾滋病毒+患者。 在众多因素中，兴奋性毒性损伤、神经免疫功能障碍、脂质紊乱和突触功能 是艾滋病毒进展和衰老过程中的主要因素。尽管所有这些非凡的发现 通过体外（破坏性）在分子水平上了解CNS中的HIV-1感染 分析，它不能直接应用于体内的大多数脑组织。非侵入性PET神经成像方法 可以填补这一空白，并提供直接和实时的相关性，上述重要的信号活动， 感染的大脑，促进新的HIV-1神经疗法。因此，我们设想直接监测兴奋性毒性， （靶点：GluN 2B-NMDA亚型）、神经炎症（P2 X7）、胆固醇（CTP 46 A1）和突触（SV 2A） 在HIV-1转基因大鼠模型的脑中，通过PET作为体内替代生物标志物发挥作用。我们推测 四种不同分子成像途径的纵向PET成像将不仅提供新的诊断， 指导治疗策略，但也研究长期艾滋病毒疾病和衰老的潜在机制， 功能失调的神经免疫系统，如“2021-2025财年NIH HIV关键研究领域”所强调的那样。