Molecular Aspects of CNS Dysfunction Due to SIV/HIV

SIV/HIV 引起的中枢神经系统功能障碍的分子方面

• 批准号: 7342048
• 负责人: HOWARD S FOX
• 金额: $ 30.68万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-10 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7342048
• 关键词: AIDS Dementia Complex; AIDS neuropathy; AMPA Receptors; Acquired Immunodeficiency Syndrome; Address; Adherence; Animals; Antiviral Agents; Autopsy; Biological Markers; Brain; Central Nervous System Diseases; Cognitive; Control Animal; Custom; Data; Dementia; Depth; Development; Diagnostic; Disease; Dose; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Goals; HIV; HIV encephalitis; HIV-1; Highly Active Antiretroviral Therapy; Human; Immunologics; Incidence; Individual; Infection; Information Systems; Investigation; Lead; Life; Longitudinal Studies; Macaca mulatta; Measurable; Measures; Metabolic; Methodology; Minor; Modeling; Molecular; Monkeys; Nervous System Physiology; Neuraxis; Neurologic; Neuronal Dysfunction; Neurons; Neuropathogenesis; Numbers; Pathogenesis; Pathology; Pathway interactions; Pattern; Phase; Plasma; Prevalence; Protocols documentation; RNA; Research; Resistance; SIV; Source; Staging; System; Techniques; Therapeutic; Treatment Protocols; Vaccine Research; Viral; Viral Load result; Virus Diseases; interest; metabolomics; mortality; motor disorder; motor impairment; nervous system disorder; novel; research study

DESCRIPTION (provided by applicant): The CNS remains a target of HIV in the era of HAART, and the effects of CNS dysfunction can be devastating. The SIV-infected monkey model for HlV-related diseases has been invaluable in studies of HIV/AIDS pathogenesis and treatment/vaccine research. We and others have developed systems and techniques to enable the study of CNS disease in SIV-infected monkeys. Using brain RNA from different stages of SIV-induced disease, we have found distinct alterations in the transcriptional profile both during the stable phase of disease, when animals are generally asymptomatic but have measurable CNS functional abnormalities, as well as in end-stage neurological disease. Here, we will first investigate 2 mechanisms for neuronal damage identified from alterations in neuronal gene expression in microarray studies. Second, using a recently developed HAART protocol, we will now study CNS function and changes in CNS gene expression during HAART treatment of SIV-infected monkeys. Furthermore, we have developed methodologies for metabolomic analysis, enabling us to perform a longitudinal study to identify significant biomarkers in plasma and CSF that correlate with CNS disease. These experiments will yield novel data, and lead to the identification of unique molecules that can then be examined in humans, as well as provide the starting point for new studies aimed at the sources of the identified metabolic differences. The identification of molecular markers for neuroAIDS is valuable for both diagnostic and etiopathogenic reasons, and we believe the recent developments in metabolomics give these techniques a distinct advantage in achieving this goal.

描述（由申请人提供）：在HAART时代，中枢神经系统仍然是HIV的靶标，中枢神经系统功能障碍的影响可能是毁灭性的。 HIV 相关疾病的 SIV 感染猴模型在 HIV/AIDS 发病机制研究和治疗/疫苗研究中具有不可估量的价值。我们和其他人开发了系统和技术来研究感染 SIV 的猴子的中枢神经系统疾病。使用 SIV 诱发疾病不同阶段的大脑 RNA，我们发现在疾病稳定期（此时动物通常无症状但具有可测量的中枢神经系统功能异常）以及终末期神经系统疾病的转录谱存在明显变化。在这里，我们将首先研究通过微阵列研究中神经元基因表达的改变确定的两种神经元损伤机制。其次，使用最近开发的HAART方案，我们现在将研究感染SIV的猴子在HAART治疗期间的中枢神经系统功能和中枢神经系统基因表达的变化。此外，我们还开发了代谢组学分析方法，使我们能够进行纵向研究，以确定血浆和脑脊液中与中枢神经系统疾病相关的重要生物标志物。这些实验将产生新的数据，并导致识别出可以在人体中进行检查的独特分子，并为针对已识别的代谢差异来源的新研究提供起点。神经艾滋病分子标记的鉴定对于诊断和病因都很有价值，我们相信代谢组学的最新发展使这些技术在实现这一目标方面具有明显的优势。