Role of novel endolysosome-dependent calcium regulatory mechanisms in HAND

新型内溶酶体依赖性钙调节机制在 HAND 中的作用

• 批准号: 8986215
• 负责人: Xuesong Chen
• 金额: $ 29.48万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-15 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8986215
• 关键词: Affect; Anti-Retroviral Agents; Calcium; Cell Death; Cells; Data; Development; Endoplasmic Reticulum; Environment; Exhibits; Functional disorder; Funding Opportunities; Genetic Transcription; Goals; HIV-1; Homeostasis; In Vitro; Individual; Infection; Lead; Life; Life Expectancy; Link; Longevity; Mission; Mitochondria; Mitotic; N-Type Calcium Channels; Nerve Degeneration; Nervous system structure; Neuraxis; Neurologic; Neuronal Injury; Neurons; Pathogenesis; Pathology; Pharmaceutical Preparations; Play; Prevalence; Preventive Intervention; Process; Proteins; Public Health; Publishing; Research; Role; Series; Structure; Surface; Synapses; System; Testing; Therapeutic; Therapeutic Intervention; Trans-Activators; Transgenic Mice; United States National Institutes of Health; Viral Proteins; Work; antiretroviral therapy; in vivo; insight; neurobehavioral; neurocognitive disorder; neuron loss; neurotoxicity; novel; novel therapeutics; prevent; public health relevance; research study

 DESCRIPTION (provided by applicant): Antiretroviral therapy (ART) has increased dramatically the life span of HIV-1 infected individuals, but damaging effects of HIV-1 persist throughout the nervous system, and the prevalence of HIV-1 associated neurocognitive disorder (HAND) is greater than 50% of HIV-1 infected people in the USA. Our long-term goal is to understand the pathogenesis of HAND and develop therapeutic interventions. The proposed studies are focused to determine novel endolysosome-dependent calcium regulatory mechanisms whereby ART drugs and HIV-1 transactivator of transcription protein (HIV-1 Tat) contribute to the development of HAND. Our central hypothesis is that elevation of endolysosome pH centrally connects ART drugs and HIV-1 Tat to the development of HAND pathology, and that ART drugs (those that elevate endolysosome pH) mimic and potentiate HIV-1 Tat-induced synaptic disruption and neuronal injury by elevating endolysosome pH and activating a novel endolysosome-dependent calcium regulatory mechanism. Guided by our preliminary findings, this novel hypothesis will be tested by pursuing three specific aims. (1) Determine, in vitro, the extent to which and mechanisms by which ART drugs and HIV-1 Tat activate a novel endolysosome-dependent calcium regulatory mechanism. (2) Determine, in vitro, the underlying mechanisms and interplay between ART drugs and HIV-1 Tat on synaptic integrity and neuronal injury. (3) Determine, in vivo, the underlying mechanisms and interplay between ART drugs and HIV-1 Tat on synaptic integrity and neuronal injury. We expect to demonstrate that endolysosomes, through novel endolysosome-dependent calcium regulatory mechanisms that is upstream of, for example, ER and mitochondrial effects of HIV-1 Tat and ART drugs, play a critical role in synaptic disruptions and neuronal injury. Such expected findings will provide novel insights into the pathogenesis of HAND, and may lead to the discovery of new effective therapeutic strategies against HAND.

 描述（由申请人提供）：抗逆转录病毒治疗（ART）显著延长了HIV-1感染者的寿命，但HIV-1的破坏性影响在整个神经系统中持续存在，并且在美国HIV-1感染者中，HIV-1相关神经认知障碍（HAND）的患病率超过50%。我们的长期目标是了解HAND的发病机制并制定治疗干预措施。拟开展的研究旨在确定ART药物和HIV-1转录反式激活蛋白（HIV-1达特）促进HAND发展的新型内溶酶体依赖性钙调节机制。我们的中心假设是，内溶酶体pH值的升高集中地将ART药物和HIV-1达特与HAND病理学的发展联系起来，并且ART药物（那些升高内溶酶体pH值的药物）通过升高内溶酶体pH值和激活新的内溶酶体依赖性钙调节机制来模拟和加强HIV-1塔特诱导的突触破坏和神经元损伤。在我们初步研究结果的指导下，这一新的假设将通过追求三个具体目标进行测试。(1)在体外确定ART药物和HIV-1达特激活新型内溶体依赖性钙调节机制的程度和机制。(2)在体外确定ART药物和HIV-1达特对突触完整性和神经元损伤的潜在机制和相互作用。(3)在体内确定ART药物和HIV-1达特对突触完整性和神经元损伤的潜在机制和相互作用。我们希望证明，通过新的内溶酶体依赖性钙调节机制，例如，ER和线粒体的作用，HIV-1达特和ART药物的上游，内溶酶体，在突触破坏和神经元损伤中发挥关键作用。这些预期的发现将为HAND的发病机制提供新的见解，并可能导致发现新的有效的治疗策略。