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

• 批准号: 9004618
• 负责人: TARIQ M RANA
• 金额: $ 76.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9004618
• 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; Life; Maintenance; Memory; Methamphetamine; Microglia; Modeling; Molecular; Nerve Degeneration; Neuraxis; Organoids; Pathogenesis; Patients; Penetration; Pharmaceutical Preparations; 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; in vivo; interdisciplinary approach; macrophage; methamphetamine abuse; methamphetamine user; nervous system disorder; neuroinflammation; novel; psychostimulant; public health relevance; regenerative; serotonin transporter; success

 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：全世界大约有 4000 万人感染人类免疫缺陷病毒。据 CDC 估计，美国有 1,144,500 名 13 岁及以上人群感染艾滋病毒，其中约 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）的出现已将艾滋病从一种致命疾病转变为一种慢性且可控制的疾病。尽管 cART 取得了成功，但 HIV 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，30-50% 的 HIV 感染者患有 HAND，仅在美国就有大约 350,000-575,000 例 HAND 病例在 cART 后持续存在，这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抗逆转录病毒药物跨血脑屏障的不同渗透率所致。众所周知，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等其他因素会加剧 HAND 的症状。甲基苯丙胺 (METH) 是一种精神兴奋药物，全世界估计有 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。手和冰毒滥用是主要的健康问题，给社会带来巨大的社会经济负担。 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体模型系统。拟议的工作将开发基于多能干细胞的脑类器官模型，并采用多学科方法来研究新型调节性非编码 RNA 和表观遗传学机制，这是生物学中的一个新兴领域，由 HAND/METH 引起的脑损伤。由于类器官具有自组织和重现体内观察到的许多再生事件的能力，因此类器官为疾病发病机制和药物测试提供了一种与人类相关、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。