Preventing and Reducing HAND by Using New BDNF Nanoprobes

使用新型 BDNF 纳米探针预防和减少手部疾病

• 批准号: 9107519
• 负责人: GORDANA D. VITALIANO
• 金额: $ 21.45万
• 依托单位: EXQOR TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-07 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107519
• 关键词: Adverse effects; Affect; Affinity; Agonist; Animal Model; Anti-Retroviral Agents; Attention; Autoradiography; Biological Markers; Biomedical Engineering; Blood; Blood - brain barrier anatomy; Brain; Brain region; Brain-Derived Neurotrophic Factor; Bypass; Calcium; Cell Proliferation; Cell Survival; Cells; Cerebrospinal Fluid; Chronic; Clathrin; Clinical Research; Cognitive; Data; Development; Diagnosis; Disease; Disease Progression; Dose; Down-Regulation; Doxycycline; Drug Carriers; Drug Delivery Systems; Drug usage; Effectiveness; Enzyme-Linked Immunosorbent Assay; Exercise; Foundations; Free Radicals; Genetic Transcription; Glucocorticoid Receptor; Glutamates; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV-associated neurocognitive disorder; Health; Hippocampus (Brain); Image; Immunohistochemistry; In Vitro; Inflammatory; Intravenous; Lead; Learning; Lymphocyte; Magnetic Resonance Imaging; Memory; Methods; Microglia; Modeling; Molecular; Molecular Abnormality; Molecular Target; Monitor; Mus; N-Methylaspartate; Nanotechnology; Nerve Degeneration; Nerve Regeneration; Neuronal Plasticity; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polyethylene Glycols; Prevention; Prevention approach; Process; Prosthesis; Proteins; Radioactive; Recovery; Reporting; Research; Research Project Grants; Resolution; Saline; Series; Severities; Signal Transduction; Small Business Innovation Research Grant; Specificity; Structure; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Trans-Activators; Transgenic Mice; Viral Proteins; anterograde transport; base; brain tissue; cognitive function; crosslink; cytokine; design; diagnostic assay; drug candidate; imaging agent; imaging biomarker; imaging modality; improved; in vivo; intraperitoneal; mouse model; nanocarrier; nanometer; nanoparticle; nanoprobe; nervous system disorder; neurocognitive disorder; neurogenesis; neuron loss; neuropsychiatry; neurotoxic; neurotoxicity; neurotrophic factor; next generation; novel; novel therapeutics; overexpression; prevent; small molecule; socioeconomics; tool

 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.

 描述（由适用提供）：人类免疫缺陷病毒（HIV）相关的神经认知障碍（HAND）代表了美国和国外的主要慢性健康问题。 MRI研究始终显示出海马的大小和与学习和记忆有关的其他大脑结构的大小减少。通过直接向CNS施用脑衍生的神经营养因子（BDNF）或使用可以间接增加BDNF的药物来实现手治疗的进展。 BDNF促进神经元可塑性并恢复大脑功能。但是，BDNF不能穿越完整的血脑屏障（BBB），并且在血液中或口服时不稳定。这项工作的目的是产生无毒的， 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.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建造，这是人体用于将分子转运到细胞的天然蛋白质。第二个成分将是BDNF蛋白药物。 BDNF将连接到载体涂层的聚乙烯乙二醇（PEG）分子上。一系列研究将确定体内纳米探针的亲和力，特异性AD功能。我们计划展示这种新型纳米技术的可行性，以预防和治疗与手相关的TAT神经毒性。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无创纳米技术工具，这可能对治疗手部有用。与现有治疗方法相比，新的纳米技术可能能够增强神经元可塑性并恢复大脑的功能，同时使用较低的治疗药物剂量并造成更少的副作用。稳定的，靶向的分子纳米探针的发展也可能为研究分子异常和手动疾病的研究提供了主要的新工具。这种新型的纳米技术可以作为可以专门针对相关大脑系统的下一代药物递送系统的基础，并且可能具有实用性作为成像剂来增强疾病的诊断和监测进展。