Preventing and Reducing HAND by Using New BDNF Nanoprobes

 描述（由申请人提供）：人类免疫缺陷病毒（HIV）相关神经认知障碍（HAND）是美国和国外的一种主要慢性健康问题。HAND的MRI研究一致显示海马体和其他与学习和记忆相关的大脑结构的大小减少。HAND的治疗进展是通过直接向CNS施用脑源性神经营养因子（BDNF）或通过使用可以间接增加BDNF的药物。BDNF促进神经元可塑性和恢复大脑功能。然而，BDNF不能穿过完整的血脑屏障（BBB），并且在血液中或口服时不稳定。这项工作的目标是生产无毒， BDNF-纳米颗粒，并测试这些纳米探针鼻内绕过BBB，靶向BDNF受体丰富的脑区域，并在与HAND相关的小鼠模型中预防或逆转HIV转录反式激活因子（达特）蛋白的神经毒性作用的假设，用多西环素诱导GT-tg双基因小鼠过表达达特蛋白。为了实现这些目标，我们将设计一个两部分的纳米探针（<50纳米）。 纳米载体将由网格蛋白构建，网格蛋白是一种天然存在的蛋白质，身体用于将分子转运到细胞中。第二种成分将是BDNF蛋白药物。BDNF将附着于包被载体的聚乙二醇（PEG）分子上。一系列的研究将确定在体内的纳米探针的亲和力，特异性和功能。我们计划证明这种新型纳米技术预防和治疗与HAND相关的达特神经毒性的可行性。如果该研究项目成功，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，可能对治疗HAND有用。新的纳米技术可能能够增强神经元的可塑性，比现有的治疗方法更快、更完全地恢复大脑功能，同时使用更低的治疗药物剂量，引起更少的副作用。开发稳定的靶向分子纳米探针也可能为研究HAND和共病疾病中的分子异常提供重要的新工具。这种新的纳米技术可以作为下一代药物输送系统的基础，可以专门针对相关的大脑系统，也可以作为成像剂，以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.