Moleclar Regulation of HIV-1 Nef Neuropathogenesis by Transforming Growth Factor Beta

转化生长因子β对 HIV-1 Nef 神经发病机制的分子调控

• 批准号: 9065364
• 负责人: Neysha Martinez-Orengo
• 金额: $ 3.26万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9065364
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Aging; Alzheimer' s Disease; Animal Model; Apoptosis; Area; Astrocytes; Autopsy; Behavior; Binding; Brain; Brain Injuries; CCL2 gene; Cell physiology; Cells; Coculture Techniques; Cognition Disorders; Cohort Studies; Comorbidity; DNA; Data; Dendritic Spines; Development; Drug toxicity; Genes; Goals; Growth; HIV; HIV-1; HIV-associated neurocognitive disorder; Health; Human; Impaired cognition; Impairment; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interruption; Investigation; Laboratories; Learning; Life; Life Expectancy; Literature; MADH4 gene; Modeling; Molecular; Molecular Models; Mononuclear; Morbidity - disease rate; Neurocognitive Deficit; Neurologic; Neuronal Plasticity; Neurons; Neuropathogenesis; Neuropsychological Tests; Nissl Bodies; Nuclear; Pathway interactions; Patients; Phagocytes; Proteins; Psyche structure; Publishing; Quality of life; Regulation; Research; Role; Signal Pathway; Signal Transduction; Staining method; Stains; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Tight Junctions; Transforming Growth Factor beta; Viral Load result; Viral Proteins; Virus Replication; antiretroviral therapy; astrogliosis; base; brain tissue; cytokine; daily functioning; design; improved; in vivo; innovation; insight; molecular modeling; monocyte; mortality; nervous system disorder; neurocognitive disorder; neuron loss; neuropathology; neurotoxic; neurotoxicity; novel; prevent; promoter; protein degradation; protein function; receptor; response; social stigma; targeted treatment; therapy adherence

DESCRIPTION (provided by applicant): Neuropathologies represent a problem for HIV-1 patients, not only due to the mental and physical limitations but also because of interference with therapy adherence. In a cohort study it was observed that the neurological impairments are not a result of drug toxicity or aging but rather suggests that there must be something else acting in the brain that provokes these milder forms of impairments [14]. The HIV-1 accessory protein negative factor (Nef) has been found to be abundantly expressed by astrocytes in postmortem brain tissue from HIV-1 patients [15]. Nef is an early viral protein required for optimal HIV replication [16, 17]. Studies suggest that Nef-induced CCL2/MCP-1 expression in astrocytes contributes to infiltration of monocytes into the brain, thereby to progression of HAD [7]. It is known that Nef is constitutively present in persistently infected astrocytes [19], but hw it exits and interacts with other cells in the brain is still an emerging area of investigation. Our long term goal is to better understand the basis of this ongoing impairment and help improve the health of HIV-1 patients that are living longer but are still confronting cognitive disorders that limit their daily tasks. The objective of this proposal is to investigate the mechanism through which Nef causes neuronal damage and understand the participation of TGFβ cascade in the inflammatory response. Since TGFβ promotes astrogliosis after brain injury [20], we want to analyze its behavior in the presence of Nef. Our central hypothesis is that HIV-1 Nef protein alters TGFβ pathway, modifying SMADs signaling while leading to increased inflammatory response and eventually neuronal damage. Our hypothesis is supported by our preliminary data and by the available literature describing the effects of Nef in the brain as well as the role of TGFβ in other neuropathologies. We have designed two aims in order to study and understand neuronal fate by TGFβ in the presence of Nef. In aim1 we will quantify the expression and activity of TGFβ signaling and consequent pro-inflammatory cytokines in neurons co-cultured with astrocytes transfected with Nef. In aim2 we will study the effects of HIV-1 Nef on astrogliosis and dendritic growth in the presence and absence of TGFβ. This study is significant since it aims to address some of those gaps that need to be filled in order to understand the action of Nef and its implication in learning impairment. The innovation of this project will provie understanding of how Nef causes cognitive disorders by altering TGFβ signaling pathway. Insight in how SMAD proteins function when exposed to Nef will help clarify how the pathway behaves in HIV-1 patients even when they have viral loads under detectable levels.

描述（由申请人提供）：神经病理学对HIV-1患者来说是一个问题，不仅是因为精神和身体上的限制，还因为对治疗依从性的干扰。在一项队列研究中，人们观察到神经损伤不是药物毒性或衰老的结果，而是表明大脑中一定有别的东西引起了这些较轻微的损伤。HIV-1附属蛋白负性因子（Nef）已被发现在HIV-1患者死后脑组织的星形胶质细胞中大量表达。Nef是HIV最佳复制所需的早期病毒蛋白[16,17]。研究表明，nef诱导星形胶质细胞中CCL2/MCP-1的表达有助于单核细胞向脑内浸润，从而促进HAD[7]的进展。众所周知，Nef存在于持续感染的星形胶质细胞[19]中，但它如何存在并与大脑中的其他细胞相互作用仍然是一个新兴的研究领域。