Center for Targeted Therapeutics 2

项目摘要 COBRE中心的主要目标是实现和加强靶向治疗领域的研究 在南卡罗来纳州的大学。这是通过提供试点研究赠款，以初级和更高 高级教师，通过资金和指导支持初级教师，并通过支持三个研究核心 （功能基因组学核心，药物设计和合成核心，显微镜和流式细胞术核心）。的 靶向治疗中心（CTT）汇集了初级和高级教师，他们对药物治疗有着共同的兴趣。 发现治疗常见和严重疾病的新分子靶点和原型药物。的 目前的项目集中于寻找治疗HIV相关神经认知障碍的疗法 （HAND）和HAND与物质使用障碍共病（SUD）。此外，该项目还解决了紧迫的 公众需要解决艾滋病毒感染者使用多种药物的问题。 根据世界卫生组织的数据，全世界有3600多万人感染艾滋病毒; 其中超过120万人在美国。艾滋病毒感染者更有可能遭受物质 使用障碍，发展成为一种被称为艾滋病毒相关神经认知障碍的临床状况。滥用药物， 特别是可卡因、芬太尼和芬太尼污染可卡因，通过协同作用增加HAND的严重性， HIV蛋白的神经毒性和潜伏HIV前病毒的重新表达。与SUD一起，艾滋病毒- 相关的认知缺陷减少了对艾滋病毒护理的参与，这加剧了健康的螺旋式下降。 status.黑人/非洲裔美国人在新诊断的艾滋病毒感染者和艾滋病患者中所占比例较高。 与其他种族和民族相比，艾滋病毒，因此患有HAND和SUD。尽管密集 研究，没有批准的治疗手，特别是对艾滋病毒和神经系统的综合影响， 滥用药物。 之前通过基于AI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HAND和HAND伴SUD合并症的再利用的候选药物。但 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治疗的新靶点。 成瘾，越来越多的赞赏艾滋病毒相关的病理管理。组合 治疗在控制HIV-1并将其从死刑转变为死刑方面取得了巨大的成功。 可控制的慢性病。同样，联合治疗是一种很有前途的方法来管理小胶质细胞状态 和HIV-1表达用于治疗SUD恶化的HAND。了解小胶质细胞的作用- 由于小胶质细胞， 特别是HIV感染的小胶质细胞参与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， 细胞外囊泡 最近，人源化动物模型和iPS分化的脑类器官已经被认为是 有前途的HAND和SUD模型。这些模型是互补的，因为它们允许我们确定 HAND的独特方面：与大脑类器官中的人类神经元和星形胶质细胞的相互作用， 与人源化动物的神经认知结果。一个多层面的合作方法，其中包括 分析动物行为、神经元结构和形态、HIV毒性的局部和远端效应，以及 与滥用药物的相互作用，是必要的，以了解疾病的复杂性，并开发新的 管理战略。 目前的项目提出了一个合作小组之间的迈克尔Shtutman博士，COBRE主任 CTT功能基因组学核心和转录组学方法和基于人工智能的药物再利用专家，博士。 Rosemarie Booze是神经炎症、SUD、HAND和HAND动物模型（USC）方面的专家。 Shilpa Buch（U.他是HAND、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 HAND的合并症和AI鉴定的化合物的测试。布兹医生的小组会专注于行为方面 和突触树突效应，Buch博士的研究小组将评估细胞内相互作用和NLRP 3- Shtutman博士的小组将专注于综合OMICS分析和化合物 对iPS分化的脑类器官的活性 该合作项目将有助于为重新利用小分子候选物奠定基础， 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.