Targeted Nano-therapeutics for Neural Regeneration

神经再生的靶向纳米治疗

• 批准号: 9279164
• 负责人: Jeoung Soo Lee
• 金额: $ 9.53万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9279164
• 关键词: Address; Adult; Antibodies; Astrocytes; Binding; Biochemistry; Biodistribution; Biomedical Engineering; Brain; Brain Injuries; Cations; Cells; Chondroitin Sulfate Proteoglycan; Chondroitinases; Clinical; Coculture Techniques; Collaborations; Complex; Cyclic AMP; Data; Deposition; Development; Drug Delivery Systems; Enzymes; FDA approved; Genes; Glycolic-Lactic Acid Polyester; Glycoproteins; Goals; Growth; Growth Inhibitors; Hybridomas; Hydrophobicity; Immunoglobulin G; Immunoglobulins; Impaired cognition; In Vitro; Injectable; Injection of therapeutic agent; Injury; Intrinsic factor; Kinetics; Ligands; Mentors; Methods; Micelles; Modeling; Modification; Molecular Analysis; Monoclonal Antibodies; Motor; Mus; Myelin; Myelin Associated Glycoprotein; Natural regeneration; Nerve Regeneration; Neuraxis; Neurites; Neuronal Plasticity; Neurons; Neurosciences; Pathology; Pattern; Pharmaceutical Preparations; Phosphodiesterase Inhibitors; Physiological; Play; Polyethyleneimine; Principal Investigator; Process; Property; Pump; RNA Binding; Rattus; Recovery of Function; Rho-associated kinase; Role; Rolipram; Sensory; Signal Transduction Pathway; Signaling Molecule; Small Interfering RNA; Specificity; Synapses; Systems Development; Therapeutic; Tissues; Transfection; Transplantation; Traumatic Brain Injury; age related; angiogenesis; animal imaging; axon growth; axonal sprouting; base; bioimaging; clinical translation; cognitive recovery; combinatorial; controlled cortical impact; copolymer; critical period; cytotoxicity; design; implantation; improved; inhibitor/antagonist; mRNA Expression; motor recovery; myelination; nanoparticle; nanotherapeutic; neonatal brain; neurodevelopment; neurogenesis; neuronal growth; novel; oligodendrocyte-myelin glycoprotein; phosphodiesterase IV; plasmid DNA; prevent; programs; protein expression; receptor; receptor binding; regenerative; response; response to injury; rho

Program Director/Principal Investigator (Last, First, Middle): Vyavahare Narendra R. Project Summary Traumatic brain injury (TBI) initiates a complex physiological response involving both progressive tissue damage and activation of reparative processes including neurogenesis, angiogenesis, and plasticity through axonal sprouting and synaptic reorganization. The limited capacity for remodeling in the adult brain is attributable to age-related changes in the extrinsic neuronal microenvironment such as accumulation of myelin- associated inhibitors (MAIs), and chondroitin sulfate proteoglycans (CSPGs), as well as intrinsic changes in neuronal biochemistry such as cyclic AMP (cAMP) levels. Several groups have begun to investigate therapeutic strategies to overcome these barriers using monoclonal antibodies against MAIs, CSPG- degradative enzymes, and drugs that modulate cAMP levels. Despite encouraging results, the clinical translation of these approaches is limited by the need for invasive delivery methods, transplantation of xenogenic cells, and use of bacterially-derived enzymes. The objective of this project is to develop novel neuron-specific nanotherapeutics for combinatorial delivery of drug and small interfering RNA (siRNA) targeting both extrinsic and intrinsic barriers to neuroplasticity. These nanotherapeutics will consist of poly (lactide-co-glycolide)-graft-polyethyleneimine (PgP) copolymer micelles loaded with 1) rolipram, phosphodiesterase inhibitor in the hydrophobic core to stabilize neuronal cAMP levels, 2) siRNA bound to the cationic shell targeting RhoA, an intracellular signaling molecule activated by multiple neuronal growth inhibitors, and 3) a monoclonal antibody against the Nogo receptor (mNgR1) that binds MAIs for neuronal targeting and inhibition of MAI/receptor binding. The Specific Aims are: 1. to synthesize and evaluate PgP- mNgR1 nanoparticles as a drug and siRNA carrier, 2. to evaluate the ability of PgP-mNgR1 nanotherapeutics loaded with rolipram and RhoA siRNA to inhibit RhoA expression, elevate cAMP, and stimulate neurite outgrowth on inhibitory substrates, and 3. to evaluate neuroplasticity and functional recovery in response to delivery of nanotherapeutics in a rat direct cortical impact model of TBI. These studies will rely upon close collaboration with the Cell, Tissue, and Molecular Analysis Core and Bioengineering and Bioimaging Core for material characterization, analysis of cell response, and animal imaging and on the expertise of the PI's mentors Drs. Mark Kindy and Michael Lynn in basic and clinical neuroscience. Through these studies, we will develop PgP as a targeted, combinatorial drug-delivery system capable of addressing the complex pathology of TBI. Due to their modular design, these NPs can be modified for use with various drugs/siRNA and targeting ligands, providing broad applicability to a diverse range of pathologies. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page

项目主任/主要研究者（最后，第一，中间）：Vyavahare Narendra R. 项目摘要 创伤性脑损伤（TBI）引发了复杂的生理反应，涉及进行性组织损伤， 损伤和修复过程的激活，包括神经发生、血管生成和可塑性， 轴突发芽和突触重组。成年人大脑重塑的能力有限， 归因于年龄相关的外在神经元微环境的变化，如髓磷脂的积累， 相关抑制剂（迈斯）和硫酸软骨素蛋白聚糖（CSPGs），以及 神经元生物化学，如环腺苷酸（cAMP）水平。几个团体已经开始调查 使用抗迈斯、CSPG-1和CSPG-2的单克隆抗体克服这些障碍的治疗策略。 降解酶和调节cAMP水平的药物。尽管结果令人鼓舞，但临床 这些方法的转化受限于对侵入性递送方法的需要， 异种细胞和细菌衍生酶的应用。该项目的目标是开发新的 用于药物和小干扰RNA（siRNA）组合递送的神经元特异性纳米治疗剂 针对神经可塑性的外在和内在障碍。这些纳米治疗剂将由聚 负载有1）咯利普兰的（丙交酯-共-乙交酯）-接枝-聚乙烯亚胺（PgP）共聚物胶束， 磷酸二酯酶抑制剂，以稳定神经元cAMP水平，2）siRNA结合的疏水核心， 靶向RhoA的阳离子外壳，一种由多种神经元生长激活的细胞内信号分子 抑制剂，和3）针对Nogo受体（mNgR 1）的单克隆抗体，其结合神经元的迈斯 靶向和抑制MAI/受体结合。具体目标是：1。合成并评价PgP- mNgR 1纳米颗粒作为药物和siRNA载体，2.评估PgP-mNgR 1纳米治疗剂的能力 负载咯利普兰和RhoA siRNA以抑制RhoA表达、升高cAMP并刺激神经突 抑制性底物上的生长，和3.评估神经可塑性和功能恢复， 在TBI的大鼠直接皮质撞击模型中递送纳米治疗剂。这些研究将依赖于密切 与细胞，组织和分子分析核心以及生物工程和生物成像核心合作， 材料表征、细胞反应分析、动物成像以及PI的专业知识 指导Mark Kindy博士和Michael林恩博士的基础和临床神经科学。通过这些研究，我们 开发PgP作为一种靶向的组合药物输送系统，能够解决复杂的病理学问题 关于TBI由于它们的模块化设计，这些NP可以被修饰用于各种药物/siRNA和靶向。 配体，提供了广泛的适用性，以各种各样的病理。 OMB编号0925-0001/0002（2012年8月批准至2015年8月31日修订版）页码续页格式页码