Neurotrophin mimetic therapeutics for HIV-associated neural dysfunction

用于治疗 HIV 相关神经功能障碍的神经营养素模拟疗法

• 批准号: 7755761
• 负责人: RICK B MEEKER
• 金额: $ 35.15万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7755761
• 关键词: Affinity; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Binding; Biological Assay; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; Calcium; Cell Survival; Central Nervous System Diseases; Central Nervous System Infections; Conditioned Culture Media; Data; Development; Dose; Epitopes; Equilibrium; Feline Immunodeficiency Virus; Functional disorder; Goals; Growth; Growth Factor; Guidelines; HIV; HIV Envelope Protein gp120; HIV-1; Highly Active Antiretroviral Therapy; Homeostasis; Impairment; In Vitro; Infection; Inflammatory; Investigation; Life; Ligands; Measures; Microglia; Microtubule-Associated Proteins; Molecular; NGFR Protein; Nature; Nerve Degeneration; Nerve Growth Factor Receptors; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurologic; Neuronal Dysfunction; Neurons; Oxidative Stress; Pathway interactions; Patients; Penetration; Peptides; Poison; Process; Property; Protein Tyrosine Kinase; Proto-Oncogene Proteins c-akt; Rattus; Receptor Activation; Receptor Protein-Tyrosine Kinases; Severities; Severity of illness; Signal Pathway; Signal Transduction; Staging; Stimulus; Supporting Cell; Symptoms; Testing; Therapeutic; Therapeutic Uses; Toxin; Transgenic Mice; Translations; Virus Diseases; Work; cellular targeting; chemokine; cytokine; design; env Gene Products; immunoreactivity; in vitro Assay; in vitro Model; in vivo; in vivo Model; indexing; macrophage; mimetics; nervous system disorder; neurodevelopment; neuron loss; neuroprotection; neurotrophic factor; pre-clinical; public health relevance; receptor expression; relating to nervous system; repaired; research study; response; small molecule; therapeutic development; transcription factor

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) rapidly penetrates into and infects the central nervous system (CNS). Inflammatory activity resulting from the interaction of HIV with macrophages and microglia in the nervous system leads to varying levels of neurological impairment and neuronal loss. While disease severity has been reduced with the advent of highly active antiretroviral therapy, CNS disease persists and is expected to exert an increasingly heavy toll as patients with HIV live longer. Currently there are no therapeutic treatments that effectively control the inflammatory interactions that disable and destroy neurons. Several studies have indicated that neurotrophin receptor activation and subsequent signaling through protein kinase B (commonly known as Akt) has substantial therapeutic potential for the treatment of HIV-associated CNS disease. However, it has been difficult to exploit this potential due to the poor penetration of peptides into the brain and difficulties in controlling the balance between neuroprotective and pro-apoptotic neurotrophin signaling. The recent identification of small, non-peptide molecules that cross the blood-brain barrier and mimic the actions of neurotrophins offers an important opportunity to develop the therapeutic potential of the neurotrophin-Akt signaling pathway. These compounds are targeted to specific epitopes of the p75 neurotrophin receptor (p75NTR) or receptor tyrosine kinase B (TrkB), thereby allowing a greater degree of control over signaling than seen with the endogenous ligands. Early work has shown that these compounds have potent neuroprotective properties. The proposed studies will use primary neural cultures to evaluate the therapeutic potential of three of these compounds. Protection against early neuronal damage will be tested by exposing rat neural cultures to conditioned medium from macrophages exposed to the HIV-1 envelope protein, gp120. Alterations in calcium homeostasis and microtubule-associated protein immunoreactivity will be used as sensitive indices of neuronal dysfunction. In addition, the direct anti- inflammatory properties of each compound will be assessed by measuring cytokine, chemokine and growth factor secretion in microglial and macrophage cultures. Assays are designed to generate basic pharmacological data needed to progress from culture experiments to pre-clinical whole animal studies. The proposed studies will establish dosing guidelines, mechanistic information and cellular targeting profiles necessary for therapeutic development of the neurotrophin mimetics. PUBLIC HEALTH RELEVANCE: Non-peptide neurotrophin mimetics represent a completely new class of compounds which penetrate effectively into the brain and offer the hope of reversing the progressive development of neural damage associated with HIV infection. By mimicking the neuroprotective and repair processes of natural neurotrophins with high potency, these compounds may offer a safe and powerful new therapy not only for HIV-associated neurodegeneration but also for a broad range of neurodegenerative diseases. The proposed studies will move these compounds closer to therapeutic use by establishing dose-response guidelines and providing detailed information on the underlying molecular and cellular pathways responsible for protection.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）迅速渗透并感染中枢神经系统（CNS）。由HIV与巨噬细胞和小胶质细胞相互作用引起的炎症活性导致神经系统障碍和神经元丧失的水平不同。尽管随着高度活跃的抗逆转录病毒疗法的出现，疾病的严重程度已降低，但随着HIV患者的寿命更长，中枢神经系统疾病持续存在，预计会造成越来越重的伤害。当前，没有治疗治疗可有效控制禁用和破坏神经元的炎症相互作用。几项研究表明，神经营养蛋白受体的激活和随后通过蛋白激酶B（通常称为AKT）的信号传导具有巨大的治疗潜力，可治疗与HIV相关的中枢神经系统疾病的治疗。但是，由于肽渗透到大脑中的渗透不足以及控制神经保护和促凋亡神经营养蛋白信号之间的平衡，因此很难利用这一潜力。最近鉴定出跨越血脑屏障并模仿神经营养蛋白的作用的小型非肽分子为发展神经营养蛋白-akt信号通路的治疗潜力提供了重要的机会。这些化合物针对p75神经营养蛋白受体（p75NTR）或受体酪氨酸激酶B（TRKB）的特定表位，从而使对信号传导的控制程度比内源配体看到的更大程度的控制。早期工作表明这些化合物具有有效的神经保护特性。拟议的研究将使用原发性神经培养物来评估其中三种化合物的治疗潜力。通过将大鼠神经培养物暴露于暴露于HIV-1包膜蛋白GP120的巨噬细胞中，可以测试对早期神经元损伤的保护。钙稳态和微管相关蛋白免疫反应性的改变将被用作神经元功能障碍的敏感指标。此外，每种化合物的直接抗炎症特性将通过测量小胶质细胞和巨噬细胞培养物中的细胞因子，趋化因子和生长因子分泌来评估。测定旨在生成从培养实验到临床前全动物研究所需的基本药理数据。拟议的研究将建立剂量指南，机理信息和细胞靶向特征，用于神经营养蛋白模拟物的治疗性开发。公共卫生相关性：非肽神经营养蛋白模拟物代表了一种全新的化合物，它们有效地渗透到大脑中，并希望扭转与HIV感染相关的神经损害的逐步发展。通过模仿具有较高效力的天然神经营养蛋白的神经保护和修复过程，这些化合物不仅可以为与HIV相关的神经变性，而且对广泛的神经退行性疾病提供安全有力的新疗法。拟议的研究将通过建立剂量反应指南，并提供有关负责保护保护的基础分子和细胞途径的详细信息，将这些化合物更接近治疗使用。