The role of novel endolysosome-dependent calcium regulatory mechanisms in HIV-1 T

新型内溶酶体依赖性钙调节机制在 HIV-1 T 中的作用

• 批准号: 8900341
• 负责人: Xuesong Chen
• 金额: $ 31.16万
• 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: 2014-08-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900341
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Calcium; Cell Death; Development; Endocytosis; Endoplasmic Reticulum; Exhibits; Funding Opportunities; Genetic Transcription; Goals; HIV-1; Health; Homeostasis; In Vitro; Individual; Lead; Life; Link; Longevity; Mediating; Mission; N-Type Calcium Channels; Nervous system structure; Neuraxis; Neurologic; Neuronal Injury; Neurons; Outcome; Pathogenesis; Peptides; Play; Prevalence; Proteins; Protons; Public Health; Research; Role; Series; Small Interfering RNA; Structure; Surface; Synapses; TRP channel; Testing; Therapeutic; Therapeutic Intervention; Trans-Activators; Transgenic Mice; United States National Institutes of Health; Viral Proteins; Work; antiretroviral therapy; effective therapy; in vivo; neurobehavioral; neurocognitive disorder; neuron loss; neurotoxicity; novel; novel therapeutics; prevent; receptor; research study

DESCRIPTION (provided by applicant): Combined antiretroviral therapy 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 the novel endolysosome-dependent mechanisms whereby HIV-1 transactivator of transcription protein (HIV-1 Tat) contributes to the development of HAND. Our central hypothesis is that HIV-1 Tat induces 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 HIV-1 Tat activates a novel endolysosome-dependent calcium regulatory mechanism. (2) Determine, in vitro, the extent to which the above endolysosome-dependent calcium regulatory mechanism underlies HIV-1 Tat-induced neuronal injury. (3) Determine, in vivo, the extent to which the above endolysosome mechanism contributes to disrupted synaptic integrity in HIV-1 Tat transgenic mice. Our results are expected to demonstrate that endolysosomes play a critical role in HIV-1 Tat-induced synaptic disruption and neuronal cell death through a novel endolysosome-dependent calcium regulatory mechanism that is upstream of previously described effects of HIV-1 Tat. Such results are expected to link together unified mechanisms causing early pathological features of HAND. Results from this work will lead to a greater understanding of HAND pathogenesis and the possible development of new therapeutics.

描述（由申请人提供）：联合抗逆转录病毒治疗显著延长了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。这些研究的重点是确定HIV-1转录反式激活蛋白（HIV-1达特）促进HAND发展的新的内溶酶体依赖性机制。我们的中心假设是HIV-1达特通过升高内溶酶体pH值和激活一种新的内溶酶体依赖性钙调节机制诱导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)在体外测定HIV-1达特在多大程度上激活了 新的内溶酶体依赖性钙调节机制。(2)在体外确定上述内溶酶体依赖性钙调节机制在多大程度上是HIV-1 Tat诱导的神经元损伤的基础。(3)在体内确定上述内溶酶体机制在多大程度上导致HIV-1达特转基因小鼠中突触完整性被破坏。我们的研究结果有望证明，内溶酶体通过一种新的内溶酶体依赖性钙调节机制，在HIV-1 Tat诱导的突触破坏和神经元细胞死亡中发挥关键作用，该机制位于先前描述的HIV-1达特效应的上游。这些结果有望将引起HAND早期病理特征的统一机制联系起来。这项工作的结果将导致对HAND发病机制的更好理解和新疗法的可能发展。