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：据 CDC 估计，全球约有 4000 万人感染了人类免疫缺陷病毒，美国有 1,144,500 名 13 岁及以上的人感染艾滋病毒，另有约 180,900 人（15.8%）已感染但未确诊。联合抗逆转录病毒疗法（cART；也称为高效抗逆转录病毒疗法，HAART）的应用已发生转变艾滋病从一种致命疾病转变为一种可控制的慢性疾病，尽管 cART 取得了成功，但艾滋病毒相关神经认知障碍 (HAND) 的高患病率给社会带来了重大挑战，据估计，有 30-50% 的艾滋病毒感染者患有这种疾病。来自 HAND 的病例，仅在美国就有大约 350,000-575,000 例 HAND 在 cART 后持续存在，可能是由于中枢神经系统中 HIV 感染的小胶质细胞和巨噬细胞储库以及不同的已知抗逆转录病毒药物穿过血脑屏障的其他因素，如 cART 的中枢神经系统毒性、大脑老化、丙型肝炎合并感染和药物滥用，会加重 HAND 的症状。据估计，全球有 2500 万人长期滥用冰毒，导致出现一系列健康并发症，包括烦躁、焦虑、高血压、精神病以及记忆力、注意力和执行功能缺陷。此外，有证据表明，冰毒可导致神经炎症和神经变性，包括多巴胺转运蛋白缺失、血清素转运蛋白缺失、多巴胺水平升高、血脑屏障破坏和冰毒药物滥用，这些都是给社会带来巨大社会经济负担的主要健康问题。 HAND 和 METH 的分子机制尚不清楚，部分原因是缺乏生理相关的人类模型系统。拟议的工作将开发基于多能干细胞的脑类器官模型并采用。类器官具有自我组织和重现体内观察到的许多再生事件的能力，因此对新型调节性非编码 RNA 和表观遗传学机制（生物学中的一个新兴领域）进行了多学科研究，以研究由 HAND/METH 引起的脑损伤。用于疾病发病机制和药物测试的相关、易于访问、可扩展的模型由于我们能够控制类器官形成和维持的微环境，因此可以研究与发育、衰老和 cART 治疗相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联，并将筛选药物以挽救由艾滋病毒和冰毒引起的突触缺陷。