NeuroAIDS Therapeutics-Targeting Immune Polarization of Macrophages in CNS

神经艾滋病治疗——针对中枢神经系统巨噬细胞的免疫极化

• 批准号: 8929300
• 负责人: Steven Daniel Douglas
• 金额: $ 104.3万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8929300
• 关键词: ADORA2B gene; ATP Hydrolysis; Abnormal Monocyte; Acquired Immunodeficiency Syndrome; Adenosine; Adjuvant; Animals; Anti-Retroviral Agents; Antiviral Agents; Blood - brain barrier anatomy; Cell Culture Techniques; Central Nervous System Diseases; Clinical; Conceptions; Cytokine Gene; Disease; Doctor of Medicine; Doctor of Philosophy; Effectiveness; Future; Gene Expression; Goals; HIV; HIV Infections; HIV vaccine; Homeostasis; Housing; Immune; Immune System Diseases; Immune response; Immunity; Impaired cognition; In Vitro; Infection; Inflammation; Inflammatory; Institution; Intervention; Joints; Lead; Leadership; Ligands; Macaca mulatta; Macrophage Colony-Stimulating Factor; Maintenance; Mental Health; Microglia; Modeling; Myelogenous; National Institute of Mental Health; Neuraxis; Neurocognitive Deficit; Neuronal Injury; Pathogenesis; Pathway interactions; Pediatric Hospitals; Peripheral; Philadelphia; Preventive; Process; Protein Tyrosine Kinase; Purinergic P1 Receptors; Reaction; Receptor Signaling; Research; Research Personnel; Research Project Grants; Resistance; Role; SIV; Signal Transduction; Source; Substance P; Substance P Receptor; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Tyrosine Kinase Inhibitor; Universities; Vaccine Design; Viral; Viral Load result; Virus; Virus Diseases; antiretroviral therapy; aprepitant; immune function; immunopathology; improved; in vivo; macrophage; medical schools; migration; monocyte; multidisciplinary; neuroAIDS; neurocognitive disorder; nonhuman primate; novel; pre-clinical; programs; public health relevance; receptor; response; therapeutic target; therapeutic vaccine; trafficking; ADORA2B gene; ATP Hydrolysis; Abnormal Monocyte; Acquired Immunodeficiency Syndrome; Adenosine; Adjuvant; Animals; Anti-Retroviral Agents; Antiviral Agents; Blood - brain barrier anatomy; Cell Culture Techniques; Central Nervous System Diseases; Clinical; Conceptions; Cytokine Gene; Disease; Doctor of Medicine; Doctor of Philosophy; Effectiveness; Future; Gene Expression; Goals; HIV; HIV Infections; HIV vaccine; Homeostasis; Housing; Immune; Immune System Diseases; Immune response; Immunity; Impaired cognition; In Vitro; Infection; Inflammation; Inflammatory; Institution; Intervention; Joints; Lead; Leadership; Ligands; Macaca mulatta; Macrophage Colony-Stimulating Factor; Maintenance; Mental Health; Microglia; Modeling; Myelogenous; National Institute of Mental Health; Neuraxis; Neurocognitive Deficit; Neuronal Injury; Pathogenesis; Pathway interactions; Pediatric Hospitals; Peripheral; Philadelphia; Preventive; Process; Protein Tyrosine Kinase; Purinergic P1 Receptors; Reaction; Receptor Signaling; Research; Research Personnel; Research Project Grants; Resistance; Role; SIV; Signal Transduction; Source; Substance P; Substance P Receptor; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Tyrosine Kinase Inhibitor; Universities; Vaccine Design; Viral; Viral Load result; Virus; Virus Diseases; antiretroviral therapy; aprepitant; immune function; immunopathology; improved; in vivo; macrophage; medical schools; migration; monocyte; multidisciplinary; neuroAIDS; neurocognitive disorder; nonhuman primate; novel; pre-clinical; programs; public health relevance; receptor; response; therapeutic target; therapeutic vaccine; trafficking

DESCRIPTION (provided by applicant): HIV infection of the central nervous system (CNS) represents an important challenge for both the treatment of neurocognitive disorders as well as the eradication of HIV infection from CNS reservoirs. The eradication of CNS reservoirs of infection will likely be beneficial, not only for treating cognitive dysfunction, but also for treament of HIV infection overall. It is clear that neurocognitive impairment is a negative predictor of survival in HIV infection, suggesting common mechanisms of viral persistence and/or pathogenesis promote both immune deficiency and neurocognitive impairment. At the intersection of both these disorders is the macrophage, where altered immune polarization can suppress antiviral immune reactions and at the same time, serve as a reservoir for viral infection in the CNS, as well as a source of inflammation and neuronal injury. This proposal is a result of a joint interactions between two NIMH supported NeuroAIDS related Centers (P30s) at Temple University (Comprehensive NeuroAIDS Center, Kamel Khalili, Ph.D., Program Director) and UPenn/Children's Hospital (Penn Mental Health Research Center, Dwight Evans, M.D., Program Director). Discussions between CHOP/UPENN and Temple investigators including Jay Rappaport, Ph.D. (Temple University), Tracy Fischer-Smith, Ph.D. (Temple University), and Steven D. Douglas, M.D., with the further interactions with Mark G. Lewis, Ph.D., Bioqual, have led to the conception of an interdisciplinary and translational program project application, investigating therapeutic approaches to eradicating HIV infected reservoirs in the CNS. The application is a multiple PI submission: Jay Rappaport, Ph.D. (Corresponding PI, Temple University) and Steven D. Douglas, M.D. (PI-Children's Hospital). This program project in response to PAR-13-267 (Novel NeuroAIDS Therapeutics, Integrated Preclinical/Clinical Program (PO1), entitled "NeuroAIDS Therapeutics-Targeting Immune Polarization of Macrophages in CNS," brings together three projects and three scientific cores, housed at three institutions. These institutions include Temple University School of Medicine, Philadelphia, PA, (Project1, Project 2, Core A and Core B), Children's Hospital of Philadelphia (Project 3 and Co-PI Core A), Bioqual Inc., Rockville, MD (Core C). There are a number of important converging concepts in each of the Projects within this program, which support the overarching hypothesis put forth in this program, that altered immune polarization of the monocyte/macrophage lineage promotes immune dysfunction and the persistence of HIV infection in the CNS and the periphery. A critical concept is the importance of interaction between the CNS and the periphery in HIV infection leading to CNS disease. These processes are centered, to a large degree, on alterations within the myeloid lineage, including peripheral monocytes, tissue macrophages, and microglia. In order to eradicate reservoirs of HIV infection, we propose the intervention within three pathways that contribute to the immune polarization of the myeloid lineage. These three approaches target the following pathways: 1) ATP hydrolysis, where the end product, adenosine, is immune suppressive (Project 1, Jay Rappaport, Ph.D., Project Leader, Temple University), 2) cFMS signaling, where M-CSF and IL-34 ligands for this receptor may contribute to abnormal monocyte/macrophage homeostasis, immune polarization, and survival of infected reservoirs, (Project 2, Tracy Fischer-Smith, Ph.D., Project Leader, Temple University) and 3) neurokinin-1 receptor signaling, where the ligand substance P appears to promote virus infection, immune polarization, survival, and CNS invasion of monocytes/macrophages and the establishment of CNS inflammatory and persistent reservoirs (Project 3, Steven D. Douglas, M.D., Project Leader, Children's Hospital of Philadelphia/UPENN). In the studies proposed in this highly integrated program project, we investigate therapeutic approaches targeting each of these pathways in studies, in vitro, ex vivo, and finally in SIV infected rhesus macaques, alone, in combination, and in the context of cART therapy. The goals and objectives of these projects are supported by an Administrative Core (Core A; Jay Rappaport, Ph.D. and Douglas, M.D., Core Co-Leaders), an Immunopathology Core (Core B; Tracy Fischer-Smith, Ph.D., Core Leader, Temple University), as well as a Non Human Primate Core (Core C; Mark G. Lewis, Ph.D., Bioqual, Inc.). It is anticipated that successful completion of the objectives of this overll program, will make important contributions toward the treatment of HIV infection and eradication of HIV reservoirs, including the CNS. It is anticipated that advances made here with further inform efforts aimed at preventive and therapeutic vaccines, where post-exposure adjuvant approaches could be employed to reactivate otherwise suppressed immune reactions.

描述（由申请人提供）：中枢神经系统（CNS）的艾滋病毒感染是治疗神经认知障碍以及从中枢神经系统储藏中消除HIV感染的重要挑战。消除中枢神经系统感染的储层可能不仅有益于治疗认知功能障碍，而且对总体上治疗HIV感染。显然，神经认知障碍是HIV感染中生存的负面预测指标，这表明病毒持久性和/或发病机理的共同机制促进了免疫缺陷和神经认知障碍。这两种疾病的交集是巨噬细胞，其中的免疫极化可以抑制抗病毒免疫反应，同时作为中枢神经系统病毒感染的储层，以及炎症和神经元损伤的来源。 该提案是两个NIMH支持的神经辅助中心（P30S）（综合性神经辅助中心，Kamel Khalili博士，计划主任）与Upenn/Children's Hospital（Penn精神健康研究中心，Dwight Evans，M.D.，M.D.，M.D.）之间的共同互动的结果。 Chop/Upenn和Temple调查人员之间的讨论包括Jay Rappaport博士。 （Temple University），Tracy Fischer-Smith博士（Temple University）和医学博士史蒂文·D·道格拉斯（Steven D. Douglas）与生物试验的马克·刘易斯（Mark G.该应用程序是多个PI提交：Jay Rappaport博士。 （坦普尔大学（Temple University）的PI相应）和医学博士Steven D. Douglas（Pi-Children's Hospital）。 This program project in response to PAR-13-267 (Novel NeuroAIDS Therapeutics, Integrated Preclinical/Clinical Program (PO1), entitled "NeuroAIDS Therapeutics-Targeting Immune Polarization of Macrophages in CNS," brings together three projects and three scientific cores, housed at three institutions. These institutions include Temple University School of Medicine, Philadelphia, PA, (Project1, Project 2, Core A核心b），费城儿童医院（项目3和Co-Pi Core A），生物Qual Inc.，Rockville，MD（Core C）（Core C）。中枢神经系统和周围的概念是中枢神经系统与周围感染中CNS疾病的相互作用的重要性。为了消除HIV感染的储层，我们提出了三种有助于髓样谱系免疫极化的途径的干预。这三种方法针对以下途径：1）ATP水解，其中最终产物腺苷是免疫抑制性的（项目1，Jay Rappaport，Ph.D.水库，（项目2，Tracy Fischer-Smith，Ph.D.，Temple University项目负责人）和3）神经运动素-1受体信号，其中配体物质P似乎促进了病毒感染，免疫极化，生存，生存和CNS侵入单核细胞/乳胶的侵害（cn），cn和Project 3 D. D. D. D. D. D.医学博士，费城儿童医院/Upenn儿童医院项目负责人。在这个高度综合的计划项目中提出的研究中，我们研究了针对研究中每种途径的治疗方法，并在体外，离体外，最后是SIV感染的恒河猕猴，仅在CART治疗中。这些项目的目标和目标得到了行政核心（核心A； Jay Rappaport博士和M.D.，M.D.，Core Core共同领导者），核心病理学核心（Core B； Tracy Fischer-Smith，Ph.D. 可以预计，成功完成该计划的目标，将为包括CNS在内的HIV感染和消除HIV水库的治疗做出重要贡献。预计在此取得的进步会通过进一步的旨在预防和治疗性疫苗的努力，在这种情况下，可以采用暴露后辅助方法将其重新激活，以重新激活其他抑制的免疫反应。