Center for Targeted Therapeutics 2

项目总结 科布雷中心的主要目标是促进和加强靶向治疗领域的研究 在南卡罗来纳大学(USC)。这是通过向初级和更多的人提供试点研究资助来实现的 高级教员，通过资金和导师支持初级教员，并支持三个研究中心 (功能基因组学核心、药物设计与合成核心、显微镜和流式细胞术核心)。这个 靶向治疗中心(CTT)聚集了初级和高级教职员工，他们对 发现治疗常见病和重特大疾病的新分子靶点和原型药物。这个 目前的项目重点是寻找治疗艾滋病毒相关神经认知障碍的疗法。 (手)和手与物质使用障碍共病(SUD)。此外，该项目解决了紧急情况 解决艾滋病毒携带者使用多种物质的公共需求。 根据世界卫生组织的数据，全世界有超过3600万艾滋病毒携带者； 这些，超过120万在美国。艾滋病毒携带者更有可能遭受物质上的痛苦 使用障碍，发展为一种被称为艾滋病毒相关神经认知障碍的临床疾病。滥用药物， 特别是可卡因、芬太尼和芬太尼污染的可卡因，通过协同作用增加手部的严重程度 HIV蛋白的神经毒性和潜伏的HIV前病毒的再次表达。与SUD、HIV- 相关的认知缺陷降低了对艾滋病毒护理的参与度，这加剧了健康状况的螺旋式下降 状态。黑人/非裔美国人在新的艾滋病毒诊断中所占比例更高， 与其他种族和族裔相比，艾滋病毒的发病率更高，因此容易患上手足口病和流行性感冒。尽管强度很大 研究表明，目前还没有批准的手部治疗方法，特别是艾滋病毒和艾滋病的联合神经影响 滥用药物。 之前，通过基于人工智能的方法，我们确定了几种化合物，包括FDA批准的 药物，作为治疗手部和手部SUD合并症的重新用途的候选药物。然而， 这种疾病的复杂性需要新的模型和先进的分子技术来确定 化合物的活性机制。 异常的小胶质细胞活性是治疗神经退行性疾病和药物的新靶点 随着对艾滋病毒相关病理疾病的管理日益重视，毒品和犯罪问题办公室也开始减少对艾滋病毒上瘾的认识。组合 治疗方法在控制HIV-1并将其从死刑转变为 可控制的慢性病。同样，联合疗法是管理小胶质细胞状态的一种很有前途的方法。 而HIV-1的表达对SUD加重的手的治疗效果更好。了解小胶质细胞的作用- 具体药物需要评估自小胶质细胞以来对组织和有机体水平的影响， 尤其是感染了HIV的小胶质细胞参与了与脑细胞的复杂相互作用：神经元、星形胶质细胞 少突胶质细胞和未感染的小胶质细胞通过细胞-细胞接触，分泌促炎因子和 胞外小泡。 最近，人源化的动物模型和iPS分化的脑器官被认为是 HAND和SUD的前景看好的模型。这些模型是互补的，因为它们允许我们确定 手的独特方面：与人脑有机体中的神经元和星形胶质细胞的相互作用 人性化动物的神经认知结果。多维协作方法，其中包括 分析动物行为、神经元结构和形态、艾滋病毒毒性的局部和远期影响，以及 与滥用药物的相互作用，对于了解疾病的复杂性和开发新的 管理策略。 目前的项目提议在Cobre主任Michael Shtutman博士的团队之间进行合作 CTT功能基因组学在转录组学方法和基于人工智能的药物再利用方面的核心和专家，Dr。 Rosemarie Booze是神经炎症、SUD、手部和手部动物模型(南加州大学)的专家。 Shilpa Buch(内布拉斯加州大学)，手部、SUD和细胞相互作用方面的专家。在项目中，我们将重点关注 HAND和SUD的分子机制，强调多物质(可卡因和芬太尼)使用障碍 手部共病和人工智能识别化合物的测试。Booze博士的团队将专注于行为方面 和突触树突效应，布赫博士的团队将评估细胞内相互作用和NLRP3- 炎症体途径，Shtutman博士的团队将专注于OMICS综合分析和化合物 IPS分化的脑有机体的活性 该合作项目将有助于为重新调整小分子候选分子的用途奠定基础 HAND/SUD治疗并加速其向临床研究的过渡。

PROJECT SUMMARY The main goal of the COBRE Center is to enable and strengthen research in the area of targeted therapeutics at the University of South Carolina (USC). This is attained by offering pilot research grants to junior and more senior faculty, by supporting junior faculty through funds and mentorship, and by supporting three research cores (Functional Genomics Core, Drug Design and Synthesis Core, and Microscopy and Flow Cytometry Core). The Center for Targeted Therapeutics (CTT) brings together junior and senior faculty with a common interest in the discovery of new molecular targets and prototype drugs for the treatment of common and serious diseases. The current project is focused on finding therapeutics for the treatment of HIV-associated neurocognitive disorder (HAND) and HAND with Substance Use Disorder comorbidities (SUD). Further, the project addresses urgent public needs addressing polysubstance use of People Living with HIV. According to the World Health Organization, more than 36 million people worldwide live with HIV; of those, more than 1.2 million are in the USA. Individuals living with HIV are more likely to suffer from substance use disorder, developing a clinical condition known as HIV-Associated Neurocognitive Disorder. Drugs of abuse, specifically cocaine, fentanyl, and fentanyl-contaminated cocaine, augment HAND's severity by synergistic neurotoxicity with HIV proteins and reemergent expression of latent HIV provirus. In conjunction with SUD, HIV- associated cognitive deficiencies decrease engagement in HIV care, which fuels a downward spiral of health status. Black/African American people account for a higher proportion of new HIV diagnoses and people with HIV, compared to other races and ethnicities, and therefore suffer from HAND and SUD. Despite intensive research, there is no approved therapy for HAND, particularly for the combined neurological effects of HIV and drugs of abuse. Previously through AI-based approaches, we determined several compounds, including FDA-approved drugs, as a candidate for the repurposing for treating HAND and HAND with SUD comorbidities. However, the complexity of the disease required new models and advanced molecular technologies to determine the mechanisms of the compounds' activities. Aberrant microglial activity is an emerging target for treating neurodegenerative diseases and drug addiction, with increasing appreciation for the management of HIV-associated pathologies. Combination therapies have had tremendous success in managing HIV-1 and converting it from a death sentence to a manageable chronic disease. Similarly, combination therapies are a promising way to manage microglia status and HIV-1 expression for the treatment of HAND worsened by SUD. Understanding the effects of microglia- specific drugs required the assessment of the effects on the tissue and organism level since microglia, specifically HIV-infected microglia involved in complex interaction with brain cells: neurons, astrocytes, oligodendrocytes, and non-infected microglia, through cell-cell contacts, secreted proinflammatory factors and extracellular vesicles. Recently, humanized animal models and iPS-differentiated cerebral organoids have been suggested as promising models of HAND and SUD. The models are complementary since they allow us to determine the unique aspects of HAND: the interaction with human neurons and astrocytes in the brain organoids and the neurocognitive outcome with the humanized animals. A multidimensional collaborative approach, which involves analysis of animal behavior, neuronal structure and morphology, local and distant effects of HIV toxicity, and interactions with drugs of abuse, is necessary to understand the complexity of the disease and to develop new management strategies. The current project proposes a collaboration between groups of Dr. Michael Shtutman, director of COBRE CTT functional genomics core and expert in transcriptomics approaches and AI-based drug repurposing, Dr. Rosemarie Booze, the expert in neuroinflammation, SUD, HAND, and HAND animal models (USC), and Dr. Shilpa Buch (U. of Nebraska) the expert in HAND, SUD and cellular interactions. In the project, we will focus on the molecular mechanism of HAND and SUD, emphasizing polysubstances (cocaine and fentanyl) use disorder comorbidity of HAND and testing of AI-identified compounds. Dr. Booze's group will focus on behavioral aspects and synaptodendritic effects, Dr. Buch's group will assess the intracellular interactions and NLRP3- inflammasome pathways, and Dr. Shtutman's group will focus on integrative OMICS analysis and compounds activities on iPS differentiated brain organoids The collaborative project will help to establish a foundation for repurposing small molecule candidates for HAND/SUD treatment and to accelerate their transition to clinical studies.