A Model of Stem Cell-Based Treatment of HIV-Related Neurological Disease

描述(由研究人员提供)：大脑是艾滋病毒感染的主要目标，参与会导致显著的神经病理变化和广泛的临床神经症状，包括艾滋病毒相关的神经认知障碍。HIV蛋白的神经毒性作用可能导致神经元退化，这可能会极大地促进认知障碍的发展。随着HAART的引入，艾滋病毒相关痴呆症的发病率有所下降，但由于认知障碍患者存活率的增加，发病率实际上有所上升。因此，必须开发出不仅能有效抑制艾滋病毒感染，而且能起到神经保护作用并有可能促进艾滋病毒引起的神经系统损伤修复的治疗方法。在这项应用中，我们将评估脑源性神经营养因子(BDNF)在抑制HIV感染后观察到的神经系统异常方面的疗效。这将利用HIV转基因大鼠模型来完成，该模型已被证明会产生特定的神经系统和免疫异常，与人类感染时看到的类似。脑源性神经营养因子是一种神经营养因子，能促进新的神经元和胶质细胞的形成，提高神经元的存活率。我们开发了一种培养CD34+骨髓干细胞(BMSCs)的纯群体的方法，并对这些细胞进行基因工程，并将它们用作将BDNF基因转移到小型哺乳动物中枢神经系统的载体。对于这些研究，我们提出了以下具体目标：目的1：建立并鉴定BMSC在HIV-1转基因(TG)大鼠中枢神经系统中的条件表达；目的2：检测转导表达BDNF的BMSC对HIV-1转基因大鼠神经系统结构和功能异常的影响。这些研究将对描述这种神经营养因子的潜在疗效以及干细胞技术在治疗与艾滋病毒感染相关的神经系统并发症中的应用具有重要意义。 公共卫生相关性：艾滋病毒感染经常与重大神经异常的发展有关。这些异常可以在含有非传染性HIV基因组的HIV-1转基因大鼠中有效地建模。在这项应用中，我们将检验脑源性神经营养因子治疗这些异常的效果，脑源性神经营养因子将由基因工程骨髓干细胞分泌，将被移植到大鼠的大脑中。

DESCRIPTION (provided by investigator): The brain is a major target for HIV infection, with involvement resulting in significant neuropathological changes and a wide range of clinical neurological symptoms, including HIV-related neurocognitive impairment. The neurotoxic effects of HIV proteins can result in neuronal degeneration which can potentially contribute significantly to the development of cognitive impairment. With the introduction of HAART the incidence of HIV associated dementia has decreased, but the prevalence has actually risen due to the increased survival of individuals with cognitive impairment. It is therefore essential to develop treatment approaches that are not only effective in suppressing HIV infection but that are also neuroprotective and can potentially promote repair of HIV-induced nervous system damage. In this application we will evaluate the efficacy of brain derived neurotrophic factor (BDNF) in suppressing nervous system abnormalities that can be observed with HIV infection. This will be done utilizing the HIV transgenic rat model, which has been shown to develop specific nervous system and immune abnormalities that are similar to those seen with the infection in humans. BDNF is a neurotrophin which promotes the development of new neuronal and glia formation and increases neuronal survival. We have developed a method for culturing a pure population of CD34+ bone marrow stem cells (BMSCs) and for genetically engineering the cells and using them as a vehicle for delivering BDNF gene into the central nervous system of small mammals. For these studies we propose the following specific aims: Aim 1: Establish and characterize conditional expression of BDNF by BMSC in the CNS of HIV-1 transgenic (Tg) rats; Aim 2: Examine the effects of the transduced, BDNF-expressing BMSC on nervous system structural and functional abnormalities in the HIV Tg rat. These studies will be important for delineating the potential efficacy of this neurotrophin and the application of stem cell technologies to the treatment of neurological complications related to HIV infection. PUBLIC HEALTH RELEVANCE: HIV infection is frequently associated with the development of significant neurological abnormalities. These abnormalities can be effectively modeled in the HIV-1 transgenic rat, which contains a non-infectious HIV genome. In this application we will examine the effect treating these abnormalities with brain derived neurotrophic factor which will be secreted by genetically engineered bone marrow stem cells that will be transplanted into the brains of the rats.