Development of Brain Organoids to Study the Impact of HIV-1, Drugs of Abuse and Aging on Cognitive Impairment

开发大脑类器官来研究 HIV-1、滥用药物和衰老对认知障碍的影响

基本信息

批准号：
10613440
负责人：
DOUGLAS F NIXON
金额：
$ 73.75万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613440
关键词：
3-Dimensional Acceleration Address Adult Affect Age Aging Alkaloids Autologous Bioinformatics Brain Brain region CCL2 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Line Cell physiology Cells Cellular Immunology Cerebral cortex Cerebrum Cicatrix Cocaine Collaborations Complex Cytotoxic T-Lymphocytes Dementia Development Disease model Drug Addiction Drug Screening Effectiveness Effector Cell Engineering Exhibits Exposure to FOXO3A gene Gene Expression Gene Expression Profile Genes Genetic Transcription Goals HIV HIV-1 HIV-associated neurocognitive disorder Hand Healthcare Systems Heterogeneity Hippocampus Human Image Immune Impaired cognition In Vitro Individual Infection Interdisciplinary Study Interleukin-1 beta Internet Lead Link Mediating Methods Microglia Microscopy Modeling Molecular Virology Nervous System Trauma Neurocognitive Deficit Neuroectoderm Neuroglia Neurons Organoids Pathogenesis Pathway interactions Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Phenotype Process Prosencephalon Reporter Reproducibility Residual state Rewards Role Signaling Protein Structure Substance abuse problem System TNF gene Technology Testing Toxic effect Variant Viral Proteins Virus aging brain analog antiretroviral therapy cell behavior cell killing cognitive testing combinatorial cortistatin drug of abuse hindbrain induced pluripotent stem cell innovation insight longevity gene mouse model neural network neuroimmunology neuroinflammation neurotoxicity nonhuman primate novel novel strategies novel therapeutics single cell analysis stem cell technology stimulant abuse tat Protein transcriptome transcriptome sequencing uptake

项目摘要

PROJECT ABSTRACT HIV-1 associated neuroinflammation and neurotoxicity lead to cognitive impairments (HIV-1-associated neurocognitive disorders or HAND) even in those under suppressive antiretroviral therapy (ART). As people living with HIV-1 age, a compounding effect is occurring, with age associated dementia added to HAND, leading to a complex web of neurocognitive deficit. This will have tremendous implications for health care systems not only in the USA but also in the developing world. How HAND develops, and how it could be modified remain mysterious, largely because It has been very difficult to study HIV-1 infection and HAND in the human brain. Over the past few years new developments in stem cell technologies have permitted the differentiation of “cerebral organoids” from induced pluripotent stem cells (iPSCs), and these cultures can be grown in vitro in conditions that promote three-dimensional expansion of neuroectoderm, in cerebral organoid or “miniature brain” forms. Cerebral organoids are heterogeneous and form a variety of brain regions, including ventral forebrain, cerebral cortex, hippocampus, and mid- and hindbrain boundary. They exhibit neurons that are functional and capable of electrical excitation, and develop microglia. These brain organoids also resemble human cortical development at the gene expression level, and allow in depth analysis of neural networks, cell behavior, drug screening, disease modeling, and variations in brain development. While brain-region composition varies in organoids from different iPSC lines, regional gene-expression patterns remain largely reproducible across individuals. These create unparalleled new opportunities to study HIV-1 infection of the brain. We propose to develop our iPSC derived organoid model which incorporates microglia, into one that better represents an adult mature brain that can support robust HIV-1 infection. With this model, we can test whether different viruses lead to differential neurotoxicity and if cells other than microglia can be latently infected with virus. We will test how individual proteins from the virus, including HIV-1 Tat causes neurological damage, and how ART or drugs such as Didehydro-Cortistatin A (dCA), which cross-neutralizes Tat activity, affects the process. Interestingly, exposure to Tat also potentiates cocaine-mediated reward mechanisms, which further promotes HAND, revealing a complex web of interactions between HIV-1 infection and drugs of substance abuse. We will determine how Tat and cocaine collaborate in neurological damage and determine if dCA can reverse it. As cerebral organoids provide a model for HIV-1 latency in the brain we can test whether administration of dCA, can “block-and-lock” any residual virus, and finally whether HIV-1 specific cytotoxic T cells (CTL) can eliminate virus in the organoid. Together, these studies promise to provide novel insights into the pathogenesis of HAND, Tat mediated neurotoxicity, effects of cocaine, and the potential link between these processes. Finally, the model promises to add exciting findings on HIV-1 latency in the brain, and if it can be silenced or eliminated.

项目摘要 HIV-1相关的神经炎症和神经毒性导致认知障碍（HIV-1相关即使在接受抑制性抗逆转录病毒治疗（ART）的患者中，也会出现神经认知障碍（HAND）。与 HIV-1 年龄一起生活，复合效应正在发生，与年龄相关的痴呆症被添加到 HAND 中，导致复杂的神经认知缺陷网络，这将对医疗保健产生巨大影响。不仅在美国而且在发展中国家的系统。修改仍然是个谜，很大程度上是因为在人类中研究 HIV-1 感染和 HAND 非常困难过去几年干细胞技术的新发展使得人类大脑成为可能。从诱导多能干细胞（iPSC）分化出“大脑类器官”，这些培养物可以在促进大脑类器官中神经外胚层三维扩张的条件下体外生长或“微型大脑”形式是异质的，形成多种大脑区域，包括腹侧前脑、大脑皮层、海马体以及中脑和后脑边界。具有功能性并能够进行电激发，并发育出这些大脑类器官。人类皮质发育在基因表达水平上，并允许深入分析神经网络、细胞行为、药物筛选、疾病建模和大脑发育的变化。来自不同 iPSC 系的类器官的组成有所不同，区域基因表达模式在很大程度上仍然存在这些为研究 HIV-1 感染创造了无与伦比的新机会。我们建议开发我们的 iPSC 衍生的类器官模型，该模型将小胶质细胞纳入其中。更好地代表了可以支持强大的 HIV-1 感染的成人成熟大脑，我们可以通过这个模型进行测试。不同的病毒是否会导致不同的神经毒性以及小胶质细胞以外的细胞是否可以潜伏我们将测试病毒的单个蛋白（包括 HIV-1 Tat）如何引起神经系统疾病。损害，以及 ART 或药物（如二脱氢皮质抑素 A (dCA)）如何交叉中和 Tat 活性，隐含地，接触 Tat 也会增强可卡因介导的奖励机制，这进一步促进了 HAND，揭示了 HIV-1 感染与药物之间复杂的相互作用网络我们将确定 Tat 和可卡因如何共同造成神经损伤，并确定是否会发生这种情况。 dCA 可以逆转这种情况，因为大脑类器官提供了大脑中 HIV-1 潜伏期的模型，因此我们可以测试是否存在这种情况。给予 dCA，可以“阻断并锁定”任何残留病毒，最后确定 HIV-1 特异性细胞毒性 T 细胞（CTL）可以消除类器官中的病毒，这些研究有望提供新的见解。 HAND 的发病机制、Tat 介导的神经毒性、可卡因的作用以及这些因素之间的潜在联系最后，该模型有望增加有关大脑中 HIV-1 潜伏期的令人兴奋的发现，以及是否可行。被压制或消除。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The chaperone protein p32 stabilizes HIV-1 Tat and strengthens the p-TEFb/RNAPII/TAR complex promoting HIV transcription elongation.

伴侣蛋白 p32 可稳定 HIV-1 Tat 并增强 p-TEFb/RNAPII/TAR 复合物，促进 HIV 转录延伸。

DOI：
发表时间：
2023-01-03
期刊：
影响因子：
11.1
作者：
Li, Chuan;Mori, Luisa P;Lyu, Shuang;Bronson, Ronald;Getzler, Adam J;Pipkin, Matthew E;Valente, Susana T
通讯作者：
Valente, Susana T

HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing.

HIV-1 缓解：加速 HIV-1 永久沉默之路。

DOI：
发表时间：
2023-10-28
期刊：
影响因子：
0
作者：
Lyons, Danielle E;Kumar, Priti;Roan, Nadia R;Defechereux, Patricia A;Feschotte, Cedric;Lange, Ulrike C;Murthy, Niren;Sameshima, Pauline;Verdin, Eric;Ake, Julie A;Parsons, Matthew S;Nath, Avindra;Gianella, Sara;Smith, Davey M;Kallas, Esper G
通讯作者：
Kallas, Esper G

Transcriptional regulation of the HIV-1 inhibitory factor human mannose receptor 1 by the myeloid-specific transcription factor PU.1.

骨髓特异性转录因子 PU.1 对 HIV-1 抑制因子人甘露糖受体 1 的转录调节。

DOI：
发表时间：
2024-01-23
期刊：
影响因子：
0
作者：
Mallorson, Rosa;Miyagi, Eri;Kao, Sandra;Sukegawa, Sayaka;Saito, Hideki;Fabryova, Helena;Morellatto Ruggieri, Luciana;Mediouni, Sonia;Valente, Susana T;Strebel, Klaus
通讯作者：
Strebel, Klaus

HIV-1 transcriptional modulation: novel host factors and prospective therapeutic strategies.

HIV-1 转录调节：新的宿主因素和前瞻性治疗策略。