Tat endolysosome escape and HAND

项目摘要 我们对TAT内溶酶体逃逸及其在TAT发病机制中的作用的认识存在根本性的差距 HIV-1相关神经认知障碍(手)。这里的目标是确定分子机制 TAT逃逸内溶体的方式，以及这种逃逸对神经毒性的影响程度。我们会 验证我们的中心假设，即TAT通过V0区形成的蛋白质孔逃避内溶酶体。 V-ATPase，这种逃逸是由内溶酶体双孔通道(TPC)释放的钙促进的， 而这种钙依赖的TAT内溶酶体逃逸过程是LTR的上游事件 反式激活是TAT诱导的神经毒性的先于和促成因素。在我们初步发现的指导下，这 新的假设将通过追求三个具体目标来检验。(1)确定v-ATPase的参与 TAT内溶酶体中的TPC逃逸。(2)确定v-ATPase和TPC在TAT诱导过程中的作用。 神经毒性。(3)确定v-ATPase和TPC在TAT诱导的学习和认知中的作用。 TAT转基因小鼠的损伤和手样病理。建议的工作具有很强的创新性。 因为它侧重于确定Tat通过蛋白质孔逃逸内溶体的机制 由v-ATPase的V0区段形成；这一过程可以由内溶酶体内释放的钙来调节。 这种新的钙依赖性TAT内溶酶体逃逸过程可能是早期和上游的事件 TAT所致的神经毒性。拟议研究的成功完成将为了解艾滋病毒-1提供新的见解 感染和手部的发病机制，并可能产生新的有效的治疗策略。

Project Abstract Fundamental gaps exist in our understanding in Tat endolysosome escape and its role in the pathogenesis of HIV-1 associated neurocognitive disorders (HAND). The objective here is to determine molecular mechanisms by which Tat escapes endolysosomes, and the extent to which this escape contributes to neurotoxicity. We will test our central hypothesis that Tat escapes endolysosomes through protein pores formed by the V0 sector of v-ATPase, that this escape is facilitated by calcium released from endolysosome two-pore channels (TPCs), and that such a calcium-dependent Tat endolysosome escape process, an upstream event of LTR transactivation, precedes and contributes to Tat-induced neurotoxicity. Guided by our preliminary findings, this novel hypothesis will be tested by pursuing three specific aims. (1) Determine the involvement of v-ATPase and TPCs in Tat endolysosome escape. (2) Determine the involvement of v-ATPase and TPCs in Tat-induced neurotoxicity. (3) Determine the involvement of v-ATPase and TPCs in Tat-induced learning and cognitive impairment as well as HAND-like pathology in Tat transgenic mice. The proposed work is highly innovative because it focuses on determining mechanisms by which Tat escapes endolysosomes via protein pores formed by V0 sector of v-ATPase; a process that can be regulated by calcium released from endolysosomes. Such a novel calcium-dependent Tat endolysosome escape process might be an early and upstream event of Tat-induced neurotoxicity. Successful completion of the proposed studies will provide novel insights into HIV-1 infection and the pathogenesis of HAND and may yield new and effective therapeutic strategies against HAND.