Immune-modifying nanoparticles for the treatment of traumatic brain injury

用于治疗创伤性脑损伤的免疫调节纳米颗粒

• 批准号: 10027888
• 负责人: JOHN A KESSLER
• 金额: $ 43.33万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027888
• 关键词: Accident and Emergency department; Acute; Address; Affect; American; Anatomy; Attenuated; Behavior; Binding; Biopolymers; Bone Marrow; Brain; Brain Injuries; Caliber; Cell Lineage; Cells; Charge; Clinical Trials Design; Cognitive; Complement; Complex; Edema; Experimental Models; FDA approved; Gene Expression; Gliosis; Glycolates; Health; Hematogenous; Hippocampus (Brain); Hour; Human; Immune; Infiltration; Inflammation; Inflammatory; Injury; Intervention; Intravenous; Label; Lead; Mediating; Microglia; Modeling; Molecular; Mus; Neuroglia; Neurons; Pharmacology; Physiological; Population; Process; Reactive Oxygen Species; Recovery; Role; Seizures; Site; Spleen; Structure; Synapses; TBI treatment; Temperature; Time; Translations; Traumatic Brain Injury; Travel; Treatment Efficacy; Tumor-infiltrating immune cells; Vascular Endothelial Cell; behavior influence; brain tissue; carboxylate; cell type; chemokine; clinically translatable; cytokine; designer receptors exclusively activated by designer drugs; excitotoxicity; experimental study; improved outcome; macrophage; monocyte; nanoparticle; neurogenesis; neuronal survival; particle; preclinical trial; preservation; prevent; protective effect; receptor; single-cell RNA sequencing; stem cell proliferation; stem cells; therapeutic development; tool; visual motor

Traumatic Brain Injury (TBI) is a major health issue. After the primary injury, there is substantial secondary injury attributable to infiltrating immune cells, cytokine release, reactive oxygen species, excitotoxicity, and other mechanisms. Despite many preclinical and clinical trials designed to limit such secondary damage, no successful therapies have emerged. However, we have found that Immune-modifying nanoParticles (IMP) are a strong candidate for a clinically translatable acute pharmacologic intervention for TBI. IMP are highly negatively charged, 500 nm-diameter particles composed of the FDA-approved biodegradable biopolymer, carboxylated poly(lactic-co-glycolic) acid (PLGA-COOH). After intravenous (IV) administration, IMP bind to the macrophage receptor with collagenous structure (MARCO) on monocytes. Monocytes bound to IMP no longer travel to sites of inflammation, but instead are sequestered in the spleen. Because IMP specifically target the MARCO+ subset of monocytes, it is distinctly different from other approaches that non-specifically target all monocyte/macrophage lineage cells including microglia. IV treatment with IMP in two different TBI models profoundly reduced the number of immune cells infiltrating into the brain, mitigated the inflammatory status of the infiltrating cells, and reduced levels of an array of cytokines and chemokines. More importantly, IMP treatment resulted in attenuated edema, preservation of brain tissue, and significant preservation of both physiologic visual and motor function. The proposed studies will examine IMP-mediated changes in gene expression that alter the inflammatory status of infiltrating cells, limit gliosis, reduce edema, and promote neuronal survival. They also will examine effects of IMP on other cell types including microglia, progenitor cells, and other immune cells. Notably, IMP are made of an FDA-approved material that is stable at room temperature and could easily be given immediately IV after TBI in the field by EMTs or in the emergency room. Mechanistically the proposed studies will help to understand more clearly the effects of infiltrating hematogenous monocyte-derived macrophages after TBI. Significantly, they also will help to develop a potentially effective and practical therapy for human TBI.

创伤性脑损伤（TBI）是一个主要的健康问题。初次受伤后，严重的继发性伤害 归因于浸润的免疫细胞，细胞因子释放，活性氧，兴奋性毒性和其他 机制。尽管旨在限制这种次要损害的临床前和临床试验，但没有成功 疗法已经出现。但是，我们发现免疫修饰的纳米颗粒（IMP）是强的 TBI的临床可翻译急性药理干预术的候选者。小鬼高度负面 由FDA批准的可生物降解生物聚合物组成的500 nm直径颗粒，羧化 聚（乳酸 - 糖）酸（PLGA-COOH）。静脉内（IV）给药后，IMP与巨噬细胞结合 单核细胞上的胶原结构（MARCO）的受体。单核细胞注定要不再前往网站 炎症，而是在脾脏中隔离。因为IMP专门针对Marco+子集 在单核细胞中，它与非特异性靶向所有单核细胞/巨噬细胞的其他方法明显不同 谱系细胞包括小胶质细胞。在两个不同的TBI模型中使用IMP治疗的IV治疗可大幅降低 免疫细胞数量浸润到大脑中，减轻浸润细胞的炎症状态，并 降低了一系列细胞因子和趋化因子的水平。更重要的是，IMP治疗导致减弱 水肿，脑组织的保存以及生理视觉和运动功能的显着保存。 拟议的研究将检查IMP介导的基因表达变化，以改变炎症状态 浸润细胞，限制神经胶质病，减少水肿并促进神经元存活。他们还将检查 对其他细胞类型的影响，包括小胶质细胞，祖细胞和其他免疫细胞。值得注意的是，小鬼是由 FDA批准的材料在室温下稳定，可以在TBI后立即立即给予IV 在EMT或在急诊室里的现场。从机械上讲，拟议的研究将有助于理解 更清楚地清楚地浸润TBI后浸润血源性单核细胞衍生的巨噬细胞的影响。显著地， 他们还将有助于为人类TBI开发潜在的有效且实用的疗法。