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

基于干细胞的 HIV 相关神经系统疾病治疗模型

• 批准号: 8130739
• 负责人: Tapas K Makar
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8130739
• 关键词: Affect; Animal Disease Models; Animals; Area; Astrocytes; Behavior; Behavioral; Bone Marrow Stem Cell; Bone Marrow Stem Cell Transplantation; Brain; Brain region; Brain-Derived Neurotrophic Factor; Butyric Acids; CD34 gene; Calcium-Binding Proteins; Cells; Clinical; Cognition; Cognitive; Congenital neurologic anomalies; Dementia; Development; Disease; Disease model; Elements; Engineering; Experimental Autoimmune Encephalomyelitis; Gene Expression; Genes; Genetic; Genome; Grant; HIV; HIV-1; Highly Active Antiretroviral Therapy; Human; Immune; Impaired cognition; Impairment; Incidence; Individual; Infection; Inflammation; Interneurons; Learning; Mammals; Mediating; Methods; Microglia; Modeling; Mus; Nerve Degeneration; Nervous System Trauma; Nervous system structure; Neuraxis; Neurocognitive; Neuroglia; Neurologic; Neurons; Neurotransmitters; Parvalbumins; Population; Prevalence; Principal Investigator; Production; Proteins; Rat Protein; Rattus; Research Personnel; Risk; Rodent; Role; Signal Pathway; Stem cells; Symptoms; System; Tetanus Helper Peptide; Therapeutic; Transgenes; Transgenic Organisms; Transplantation; Viral Proteins; Virus; Virus Diseases; base; cellular transduction; clinical effect; cognitive function; frontal lobe; genetically modified cells; immune function; improved; macrophage; mature animal; mortality; nervous system disorder; neuronal survival; neuroprotection; neurotoxic; neurotrophic factor; novel strategies; peripheral blood; prevent; programs; protective effect; protein expression; public health relevance; repaired; stem cell technology; tumor

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.

描述（由研究者提供）：大脑是HIV感染的主要靶点，其受累导致显著的神经病理学变化和广泛的临床神经系统症状，包括HIV相关的神经认知障碍。HIV蛋白的神经毒性作用可导致神经元变性，这可能显著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的生存率增加，患病率实际上有所上升。因此，至关重要的是开发治疗方法，不仅有效地抑制艾滋病毒感染，但也是神经保护，并可能促进修复艾滋病毒引起的神经系统损伤。在本申请中，我们将评估脑源性神经营养因子（BDNF）抑制神经系统异常，可以观察到与艾滋病毒感染的疗效。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与人类感染相似的特定神经系统和免疫异常。BDNF是一种神经营养因子，其促进新神经元和神经胶质形成的发育并增加神经元存活。我们已经开发出一种培养纯CD 34+骨髓干细胞（BMSC）群体的方法，并对这些细胞进行基因工程改造，并使用它们作为将脑源性神经营养因子基因递送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：建立和表征条件表达BDNF的BMSC在中枢神经系统的HIV-1转基因（Tg）大鼠;目的2：检查转导，BDNF表达BMSC对神经系统的影响HIV Tg大鼠的结构和功能异常。这些研究对于阐明这种神经营养因子的潜在功效以及干细胞技术在治疗与HIV感染相关的神经系统并发症中的应用将非常重要。 公共卫生相关性：HIV感染通常与显著的神经系统异常的发展相关。这些异常可以在HIV-1转基因大鼠中有效地建模，其含有非感染性HIV基因组。在本申请中，我们将检查用脑源性神经营养因子治疗这些异常的效果，该脑源性神经营养因子将由基因工程骨髓干细胞分泌，该骨髓干细胞将被移植到大鼠的大脑中。