Targeted Nano-therapeutics for Neural Regeneration

神经再生的靶向纳米治疗

基本信息

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
项目类别：
财政年份：
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

项目摘要

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

项目总监/首席研究员（最后、第一、中间）：Vyavahare Narendra R. 项目概要创伤性脑损伤 (TBI) 会引发复杂的生理反应，涉及进展性组织修复过程的损伤和激活，包括神经发生、血管生成和可塑性轴突萌芽和突触重组。成人大脑的重塑能力有限归因于与年龄相关的外在神经元微环境的变化，例如髓磷脂的积累相关抑制剂（MAI）和硫酸软骨素蛋白聚糖（CSPG），以及内在变化神经元生物化学，例如环磷酸腺苷 (cAMP) 水平。多个团体已开始调查使用针对 MAI、CSPG 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到对侵入性递送方法、移植的需要的限制。异种细胞，以及细菌衍生酶的使用。该项目的目标是开发新颖的用于药物和小干扰 RNA (siRNA) 组合递送的神经元特异性纳米疗法针对神经可塑性的外在和内在障碍。这些纳米疗法将由聚 (丙交酯-共-乙交酯)-接枝-聚乙烯亚胺(PgP)共聚物胶束负载有1)咯利普兰，疏水核心中的磷酸二酯酶抑制剂可稳定神经元 cAMP 水平，2) siRNA 与靶向 RhoA 的阳离子壳，RhoA 是一种由多个神经元生长激活的细胞内信号分子抑制剂，以及 3) 针对 Nogo 受体 (mNgR1) 的单克隆抗体，该抗体与神经元的 MAI 结合 MAI/受体结合的靶向和抑制。具体目标是： 1. 合成和评估 PgP- mNgR1纳米颗粒作为药物和siRNA载体，2.评估PgP-mNgR1纳米治疗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 3. 抑制性底物的生长，评估神经可塑性和功能恢复在 TBI 大鼠直接皮质影响模型中提供纳米治疗药物。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 的专业知识导师博士。马克·金迪（Mark Kindy）和迈克尔·林恩（Michael Lynn）研究基础和临床神经科学。通过这些研究，我们将将 PgP 开发为能够解决复杂病理学的靶向组合药物输送系统脑外伤性脑损伤 (TBI)。由于其模块化设计，这些 NP 可以进行修改，以与各种药物/siRNA 和靶向一起使用配体，为各种病理学提供了广泛的适用性。 OMB 编号 0925-0001/0002（修订版 08/12 已批准至 8/31/2015）页面延续格式页面