Neurotrophin mimetic therapeutics for HIV-associated neural dysfunction

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与神经系统中的巨噬细胞和小胶质细胞相互作用引起的炎症活动导致不同程度的神经损伤和神经元损失。虽然随着高活性抗逆转录病毒疗法的出现，疾病的严重程度已经降低，但中枢神经系统疾病仍然存在，并且随着艾滋病毒患者寿命的延长，预计将造成越来越严重的损失。目前还没有治疗方法可以有效地控制炎症相互作用，使神经元丧失功能和破坏。一些研究表明，神经营养因子受体激活和随后通过蛋白激酶B（通常称为Akt）的信号传导在治疗hiv相关中枢神经系统疾病方面具有巨大的治疗潜力。然而，由于多肽对大脑的渗透能力差，以及难以控制神经保护和促凋亡神经营养因子信号传导之间的平衡，开发这种潜力一直很困难。最近发现的小的非肽分子可以穿过血脑屏障，模拟神经营养因子的作用，这为开发神经营养因子- akt信号通路的治疗潜力提供了重要的机会。这些化合物靶向p75神经营养因子受体（p75NTR）或受体酪氨酸激酶B （TrkB）的特异性表位，从而比内源性配体更大程度地控制信号传导。早期的研究表明，这些化合物具有强大的神经保护作用。拟议的研究将使用初级神经培养来评估这三种化合物的治疗潜力。对早期神经元损伤的保护将通过将大鼠神经培养物暴露于暴露于HIV-1包膜蛋白gp120的巨噬细胞的条件培养基中来测试。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特性将通过测量细胞因子、趋化因子和生长因子在小胶质细胞和巨噬细胞培养中的分泌来评估。实验旨在产生从培养实验到临床前全动物研究进展所需的基本药理学数据。拟议的研究将为神经营养因子模拟物的治疗发展建立剂量指南、机制信息和细胞靶向概况。公共卫生相关性：非多肽神经营养因子模拟物代表了一类全新的化合物，可以有效地渗透到大脑中，并为逆转与HIV感染相关的神经损伤的进行性发展提供了希望。通过高效模仿天然神经营养素的神经保护和修复过程，这些化合物可能不仅为hiv相关的神经退行性疾病，而且为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-反应指南和提供负责保护的潜在分子和细胞途径的详细信息，使这些化合物更接近治疗用途。

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.