Role of p53 family in neuropathogenesis in AIDS

p53 家族在 AIDS 神经发病机制中的作用

• 批准号: 7555586
• 负责人: BASSEL E SAWAYA
• 金额: $ 37.5万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555586
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; Acetylation; Acquired Immunodeficiency Syndrome; Affect; Animal Model; Apoptosis; Apoptotic; Astrocytes; Attenuated; Autopsy; Biological Assay; Brain; Cell Death; Cell Line; Cell physiology; Cells; Cerebrospinal Fluid; Cessation of life; Cognitive; Cultured Cells; DNA Binding; DNA-dependent protein kinase; Data; Dementia; Development; Disease; EMSA; Environment; Family; Family member; Gene Expression; HIV; HIV encephalitis; HIV-1; Highly Active Antiretroviral Therapy; Human; Impaired cognition; Incidence; Injury; Integration Host Factors; Investigation; Lead; Light; Link; Lysine; MAP Kinase Gene; Measures; Microglia; Minor; Mitochondria; Modeling; Modification; Molecular; Nerve Degeneration; Neuronal Dysfunction; Neuronal Injury; Neurons; Neuropathogenesis; Outcome; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Positive Transcriptional Elongation Factor B; Post-Translational Protein Processing; Prevalence; Protein p53; Proteins; Public Health; Role; Site; Staging; TP53 gene; Testing; Therapeutic; Time; Tissues; Translating; Translations; Tumor Suppressor Proteins; Viral Proteins; antiretroviral therapy; base; cofactor; design; genetic regulatory protein; gray matter; improved; inhibitor/antagonist; macrophage; motor disorder; mutant; nervous system disorder; neuron loss; neurotoxic; neurotoxicity; novel therapeutics; prevent; promoter; protein degradation; protein p73; research study; tat Protein

DESCRIPTION (provided by applicant): Despite the use of Highly active antiretroviral therapy (HAART), neuronal cell death remains a problem that is frequently found in the brains of HIV-1-infected patients. HAART has successfully prevented many of the former end-stage complications of AIDS, however, with increased survival times, the prevalence of minor HIV-associated cognitive impairment appears to be rising among AIDS patients. Further, HIV encephalitis (HIVE) is still prevalent in treated patients as well as attenuated forms of HIVE and CNS opportunistic disorders. HIV-associated cognitive impairment correlates with the increased presence in the CNS of activated, though not necessarily HIV-1- infected, microglia and CNS macrophages. This suggests that indirect mechanisms of neuronal injury and loss/death occur in HIV/AIDS as a basis for dementia since neurons are not themselves productively infected by HIV-1. Recent evidence indicates that the p53 tumor suppressor protein and its related family member, p73, play an essential role in regulating neuronal loss/apoptosis. The mechanisms involved in induction of p53 or p73 which lead to dendritic retraction and neuronal loss are not fully elucidated. Increased levels of p53 were observed in the neurons of AIDS patients, which may be connected to the occurrence of HIV-1-associated dementia (HAD) in those patients. Similar to p53 activation in neurons, p53 activation in microglia and astrocytes may also contribute to alterations in the physiology of these cells that eventually result in a neurotoxic environment and neuronal loss. Importantly, for p53 to be functional and stable, activated p73 is required. Based on this finding, we have studied the relationship between p73 and Tat, and have demonstrated the ability of HIV-1 in general and of Tat in particular, to induce the endogenous levels of p73. P73 induction prevents acetylation of Tat on lysine 28 through their direct physical interaction, which also inhibits Tat's apoptotic activity. The association of Tat with p73 also reduces Tat-activation of the HIV- 1 LTR, and prevents p73 from causing cell death in astrocytes. These data suggest a basis for the restricted replication of HIV-1 in astrocytes. We also investigated the interplay between Tat and p73 in neuronal cells. Surprisingly, Tat was unable to promote neuronal death in the absence of either p73 or p53, suggesting a strong link between Tat, p73, p53 and neuronal cell death. Hence, we now propose to study the mechanism(s) whereby Tat induces p73. This will include analysis of control of the p73 promoter and of p73 protein turnover. We will also examine whether induction of p73 by Tat leads to activation of p53 and induction of neuronal cell death. The outcome from the proposed studies should provide new information regarding mechanisms of neuronal loss in AIDS patients and suggest possible new therapeutic approaches. PUBLIC HEALTH RELEVANCE This proposal focuses on the relationship between the HIV-1 regulatory protein, Tat, and cellular factors. The results of these studies will highlight the pathways used by Tat to cause damage to neurons and lead to new avenues for the development of safe and effective therapeutic approaches to inhibit neurodegeneration seen in AIDS patients.

描述（由申请人提供）：尽管使用了高效抗逆转录病毒疗法（HAART），但神经元细胞死亡仍然是HIV-1感染患者大脑中常见的问题。HAART已经成功地预防了艾滋病的许多前终末期并发症，然而，随着生存时间的增加，艾滋病患者中与艾滋病毒相关的轻微认知障碍的患病率似乎正在上升。此外，HIV脑炎（HIVE）在治疗的患者中以及减弱形式的HIVE和CNS机会性病症中仍然普遍存在。HIV相关的认知障碍与CNS中活化的（但不一定是HIV-1感染的）小胶质细胞和CNS巨噬细胞的存在增加相关。这表明，神经元损伤和损失/死亡的间接机制发生在艾滋病毒/艾滋病作为痴呆症的基础，因为神经元本身并没有被HIV-1感染。最近的证据表明，p53肿瘤抑制蛋白及其相关家族成员p73在调节神经元损失/凋亡中起重要作用。诱导p53或p73导致树突回缩和神经元丢失的机制尚未完全阐明。在艾滋病患者的神经元中观察到p53水平增加，这可能与这些患者中HIV-1相关痴呆（HAD）的发生有关。与神经元中的p53激活类似，小胶质细胞和星形胶质细胞中的p53激活也可能导致这些细胞的生理学改变，最终导致神经毒性环境和神经元损失。重要的是，为了使p53发挥功能和稳定，需要激活p73。基于这一发现，我们研究了p73和达特之间的关系，并证明了HIV-1一般和达特特别诱导内源性p73水平的能力。P73诱导通过它们的直接物理相互作用阻止赖氨酸28上的达特的乙酰化，这也抑制了达特的凋亡活性。达特与p73的结合也减少了HIV- 1 LTR的塔特激活，并防止p73引起星形胶质细胞中的细胞死亡。这些数据表明，在星形胶质细胞中的HIV-1的限制性复制的基础。我们还研究了神经细胞中达特和p73之间的相互作用。令人惊讶的是，达特在p73或p53不存在的情况下不能促进神经元死亡，这表明达特、p73、p53和神经元细胞死亡之间有很强的联系。因此，我们现在建议研究达特诱导p73的机制。这将包括分析p73启动子和p73蛋白周转的控制。我们还将研究达特诱导p73是否导致p53的激活和神经元细胞死亡的诱导。从拟议的研究结果应该提供新的信息艾滋病患者的神经元损失的机制，并提出可能的新的治疗方法。公共卫生相关性本提案的重点是HIV-1调节蛋白达特和细胞因子之间的关系。这些研究的结果将突出达特用于造成神经元损伤的途径，并为开发安全有效的治疗方法以抑制艾滋病患者中出现的神经变性开辟新的途径。