Preventing and Reducing HAND by Using New BDNF Nanoprobes

 描述(申请人提供)：人类免疫缺陷病毒(HIV)相关的神经认知障碍(HAND)在美国和国外都是一个主要的慢性健康问题。对手的核磁共振研究一直显示，海马体和其他与学习和记忆相关的大脑结构的大小都有所减小。通过将脑源性神经营养因子(BDNF)直接应用于中枢神经系统，或通过使用可间接增加BDNF的药物，手部的治疗已取得进展。脑源性神经营养因子可促进神经元的可塑性，恢复大脑功能。然而，BDNF不能穿过完整的血脑屏障(BBB)，在血液中或口服时不稳定。这一努力的目标是生产无毒、 为了测试这些纳米探针在鼻腔内绕过血脑屏障，靶向BDNF受体丰富的脑区，以及防止或逆转HIV反式转录激活物(TAT)蛋白的神经毒性作用的假设，在与手相关的小鼠模型中，GT-TG双基因小鼠用多西环素诱导TAT蛋白过表达。为了实现这些目标，我们将设计一个由两部分组成的纳米探测器(&lt；50纳米)。一种纳米载体将由网状蛋白构成，这种蛋白质是人体用来将分子输送到细胞内的一种自然产生的蛋白质。第二种成分将是BDNF蛋白药物。BDNF将附着在包覆载体的聚乙二醇分子上。一系列研究将在体内确定纳米探针的亲和力、特异性和功能性。我们计划证明这种新的纳米技术在预防和治疗与手相关的神经毒性方面的可行性。如果这项研究项目成功，它将为预防和治疗神经毒性提供新的非侵入性纳米技术工具，这可能对治疗手有用。与现有的治疗方法相比，这项新的纳米技术可能能够更快、更彻底地增强神经元的可塑性和恢复大脑功能，同时使用更低的治疗药物剂量，并产生更少的副作用。稳定的、靶向的分子纳米探针的发展也可能为研究手部的分子异常和共病疾病提供一个重要的新工具。这种新颖的纳米技术可以作为下一代药物输送系统的基础，这种系统可以专门针对相关的大脑系统，也可能作为一种成像试剂来加强诊断和监测疾病的进展。

 DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) associated neurocognitive disorder (HAND) represents a major chronic health problem in the US and abroad. MRI studies of HAND consistently show a decrease in the size of the hippocampus and other brain structures associated with learning and memory. Advances in treatment of HAND have been made by administering brain derived neurotrophic factor (BDNF) directly to the CNS, or by using drugs that can increase BDNF indirectly. BDNF promotes neuronal plasticity and restores brain functions. However, BDNF cannot cross an intact blood brain barrier (BBB), and is unstable in the blood or when delivered orally. The goal of this effort is to produce non-toxic, BDNF-nanoparticles, and to test the hypothesis that these nanoprobes bypass the BBB intranasally, target BDNF receptor rich brain regions, and prevent or reverse neurotoxic effects of HIV transactivator of transcription (tat) protein in a mouse model relevant to HAND, the GT-tg bigenic mouse induced with doxycycline to overexpress tat protein. To accomplish these goals we will design a two-part nanoprobe (<50 nanometers). A nanocarrier will be constructed out of clathrin, a naturally occurring protein the body uses for transporting molecules into cells. The second component will be a BDNF protein drug. BDNF will be attached to polyethylene glycol (PEG) molecules coating the carrier. A series of studies will ascertain the affinity, specificity ad functionality of the nanoprobes in vivo. We plan to demonstrate the feasibility of this novel nanotechnology to prevent and treat tat neurotoxicity associated with HAND. If this research project is successful it will provide new noninvasive nanotechnology tools for prevention and treatment of neurotoxicity that may be useful for treating HAND. The new nanotechnology may be able to enhance neuronal plasticity and restore brain functions more quickly and completely than existing treatment methods, while using much lower therapeutic drug doses and causing fewer side effects. The development of a stable, targeted molecular nanoprobe may also provide a major new tool for research of molecular abnormalities in HAND and co-morbid disorders. This novel nanotechnology may serve as the basis for a next generation drug-delivery system that can specifically target relevant brain systems, and also may have utility as an imaging agent to enhance diagnosis and monitor progression of the disease.