Modeling HIV/AIDS Associated Neurological Disorders with Human Pluripotent Cells

用人类多能细胞模拟艾滋病毒/艾滋病相关的神经系统疾病

基本信息

批准号：
9635762
负责人：
TARIQ M RANA
金额：
$ 77.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9635762
关键词：
13 year old AIDS/HIV problem Acquired Immunodeficiency Syndrome Aging Agitation Anti-Retroviral Agents Anxiety Area Attention Biological Models Biology Blood - brain barrier anatomy Brain Brain Injuries Cells Centers for Disease Control and Prevention (U.S.)Cerebrum Chronic Data Defect Development Disease model Dopamine Drug abuse Epigenetic Process Event Exhibits HIV HIV Infections HIV-associated neurocognitive disorder Health Hepatitis C co-infection High Prevalence Highly Active Antiretroviral Therapy Human Hypertension Individual Lead Maintenance Memory Methamphetamine Microglia Modeling Molecular Nerve Degeneration Neuraxis Organoids Pathogenesis Patients Penetration Pharmaceutical Preparations Physiological Pluripotent Stem Cells Psychotic Disorders Societies Substance abuse problem Symptoms Synapses Toxic effect United States Untranslated RNA Work aging brain antiretroviral therapy base dopamine transporter drug testing executive function human model in vivo interdisciplinary approach macrophage methamphetamine abuse methamphetamine user nervous system disorder neuroinflammation novel psychostimulant public health relevance regenerative serotonin transporter socioeconomics success

项目摘要

DESCRIPTION: Approximately 40 million people worldwide are infected with human immunodeficiency virus. According to the CDC estimates, 1,144,500 people aged 13 years and older are living with HIV infection in the USA, with ~180,900 (15.8%) others infected but undiagnosed. The advent of combination antiretroviral therapy (cART; also known as highly active antiretroviral therapies, HAART) has transformed AIDS from a fatal illness into a chronic and manageable condition. Despite the success of cART, high prevalence of HIV-associated neurocognitive disorders (HAND) poses a major challenge for the society. It is estimated that 30-50% of individuals with HIV suffer from HAND, and approximately 350,000-575,000 cases in the United States alone HAND persist after cART likely due to the HIV infected microglia and macrophage reservoirs in the central nervous system and variable penetration of anti-retroviral drugs across the blood brain barrier. Additional factors such as CNS toxicity of cART, the aging of the brain, hepatitis C co-infection and substance abuse are known to exacerbate the symptoms of HAND. Methamphetamine (METH) is a psychostimulant drug that is chronically abused by an estimated 25 million people in the world. METH users exhibit an array of health complications ranging from agitation, anxiety, hypertension, psychosis and deficits in memory, attention and executive functions. Moreover, evidence suggests that METH can lead to neuroinflammation and neurodegeneration including loss of dopamine transporters, loss of serotonin transporters, increased dopamine levels, breakdown of the blood brain barrier. HAND and METH drug abuse are major health problems with huge socioeconomical burdens on society. Molecular mechanisms of HAND and METH are not well understood, partly due to the lack of physiologically relevant human model systems. Proposed work will develop pluripotent stem cell based cerebral organoid models and employ multidisciplinary approaches to investigate novel regulatory non-coding RNAs and epigenetics mechanisms, a nascent area in biology, of brain injury caused by HAND/METH. Because of their ability to self-organize and recapitulate many regenerative events seen in vivo, organoids present a human relevant, easily accessible, scalable model for disease pathogenesis and drug testing. Since we are able to control the microenvironment of organoid formation and maintenance, brain functions under various human conditions related to development, aging, and cART treatments can be studied. Results will be correlated with patients' data and drugs will be screened to rescue synaptic defects caused by HIV and METH.

描述：全世界约有4000万人感染了人类免疫缺陷病毒。根据疾病预防控制中心的估计，在美国，有1,144,500名13岁以上的人患有艾滋病毒感染，约有180,900（15.8％）受感染但未诊断。联合抗逆转录病毒疗法的冒险（卡车；也称为高度活跃的抗逆转录病毒疗法，HAART）将艾滋病从致命疾病转变为慢性且易于控制的疾病。尽管购物车取得了成功，但与艾滋病毒相关的神经认知障碍（Hand）的高流行率对社会构成了重大挑战。据估计，仅在美国，仅在美国，仅在美国，就有30-50％的艾滋病毒患者遭受了手的痛苦，大约350,000-575,000例手工可能是由于中枢神经系统中艾滋病毒感染的小胶质细胞和巨噬细胞储量引起的，以及在血液脑障碍物中抗逆转录病毒药物的可变渗透。众所周知，诸如CNS的毒性，大脑衰老，肝炎共感染和药物滥用等其他因素会加剧手的症状。甲基苯丙胺（甲基苯丙胺）是一种精神刺激药物，在世界上估计有2500万人长期滥用。冰毒使用者表现出一系列健康并发症，包括躁动，焦虑，高血压，精神病以及记忆，注意力和执行功能的定义。此外，有证据表明，甲基苯丙胺可以导致神经炎症和神经退行性变化，包括多巴胺转运蛋白的丧失，5-羟色胺转运蛋白的丧失，增加多巴胺水平的升高，血液脑屏障的崩溃。在社会上，手和甲基药物滥用是巨大的社会经济伯恩斯的主要健康问题。手和甲基甲基的分子机制尚未得到很好的理解，部分原因是缺乏与物理相关的人类模型系统。拟议的工作将开发多能干细胞的大脑器官模型和员工多学科方法，以研究新型的调节性非编码RNA和表观遗传学机制，这是生物学的新生区域，脑损伤的新生区域。由于它们能够自我组织和概括体内看到的许多再生事件，因此，器官提出了人类相关的，易于接近的，可访问的，可扩展的，用于疾病发病机理和药物测试。由于我们能够控制器官形成和维护的微环境，因此可以研究与发育，衰老和手推车治疗有关的各种人类条件下的大脑功能。结果将与患者的数据相关，并将筛选药物以挽救由HIV和METH引起的突触缺陷。