Enabled by drug delivery: Studying the role of brain-resident and infiltrating myeloid cell phenotype in brain damage associated with inflammatory disease

通过药物输送实现：研究大脑驻留和浸润性骨髓细胞表型在炎症性疾病相关脑损伤中的作用

• 批准号: 10714766
• 负责人: John R Clegg
• 金额: $ 37.33万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714766
• 关键词: Acute; Acute Brain Injuries; Address; Anatomy; Anti-Inflammatory Agents; Autoimmune; Autoimmune Diseases; Award; Basic Science; Biodistribution; Blood; Blood Circulation; Brain; Brain Injuries; Cells; Central Nervous System; Chronic; Circulation; Development; Disease; Drug Delivery Systems; Drug usage; Encapsulated; Encephalitis; Exposure to; Hydrogels; Immune; Implant; Infiltration; Inflammation; Inflammatory; Injectable; Injections; Interferon Type II; Interleukin-10; Investments; Leukocytes; Macrophage; Mentors; Microglia; Mus; Myeloid Cells; NanoGel; Neurologic Deficit; Neutrophil Activation; Patients; Peripheral; Phenotype; Process; Prophylactic treatment; Proteins; Reaction; Resources; Role; Scientist; Technology; Therapeutic; Time; Tissues; Toxin; Training; Traumatic injury; Variant; Virus Diseases; biomaterial compatibility; brain fog; brain parenchyma; brain tissue; crosslink; cytokine; experience; immune activation; immune cell infiltrate; immunoregulation; implantation; insight; interdisciplinary collaboration; invention; monocyte; monomer; mouse model; neutrophil; targeted treatment

Project Summary: Patients inflicted with a traumatic injury, autoimmune disease, viral infection, or prolonged exposure to toxins often experience acute brain damage, resulting in functional and anatomical changes within the brain. Scientists have uncovered two key mechanisms through which innate immune cells drive acute brain damage: infiltration of activated neutrophils and monocytes into the brain parenchyma from systemic circulation, and chronic activation of brain-resident microglia. However, there is a basic science ‘gap’ in our understanding of these overlapping inflammatory processes, which complicates the development of targeted therapeutics. To what extent are the brain resident microglia, as opposed to infiltrating blood-derived myeloid cells, responsible for acute brain injury in inflammatory disease? To address this overarching question, we invented two enabling drug delivery technologies. The first technology is a biocompatible and biodegradable nanogel, comprised of covalently crosslinked acrylic monomers, which delivers active protein specifically to macrophages. We will leverage this material to answer our first key question: To what extent is peripheral activation responsible for immune cell infiltration of the central nervous system (CNS) parenchyma? We hypothesize that monocyte and neutrophil activation within circulation will induce central infiltration in healthy mice, while exacerbating infiltration in inflammatory disease. We will optimize immunomodulatory variations of the nanogel to activate circulating innate immune cells toward inflammation (interferon gamma) versus tolerance (interleukin 10). We will evaluate the extent to which circulating innate immune cell activation using targeted nanogels influences the cells’ biodistribution within healthy mice and mouse models of inflammatory disease. The second technology is an injectable hydrogel encapsulating cytokines and donor macrophages that is suitable for intracerebral implantation. Through direct injection of immunomodulatory proteins and myeloid cells into the parenchyma of healthy mice, we will evaluate the impact of infiltrating myeloid cell phenotype on brain-resident microglia separate from any activation within or infiltration from the periphery. We will quantify the extent to which classically versus alternatively polarized macrophages, implanted within the brain parenchyma, activate brain- resident microglia toward inflammation and induce neurological deficit (i.e. functional, anatomical). As proof-of- concept, we will evaluate local delivery of anti-inflammatory cytokines and macrophages as a prophylactic treatment for inflammatory brain damage associated with an LPS challenge. The MIRA award will allow the PI (Clegg) to commit greater time and resources to these unanswered questions, interdisciplinary collaborations, training, and mentoring of a diverse scientific workforce. We anticipate that long-term investment in this line of inquiry will result in fundamental insights on the mechanism of inflammation-induced brain injury as well as translational technologies for specific disease indications.

项目概述：患有创伤性损伤、自身免疫性疾病、病毒感染或长期 暴露于毒素往往经历急性脑损伤，导致功能和解剖结构的变化， 大脑科学家们发现了先天免疫细胞驱动急性大脑的两种关键机制 损伤：活化的中性粒细胞和单核细胞从体循环渗入脑实质， 以及大脑中小胶质细胞的慢性激活。然而，在我们的理解中， 这些重叠的炎症过程，这使靶向治疗的发展复杂化。到 与浸润血液来源的骨髓细胞相比， 导致炎症性疾病中急性脑损伤为了解决这个首要问题，我们 发明了两种药物输送技术第一项技术是生物相容性和生物降解性 纳米凝胶，由共价交联的丙烯酸单体组成，其将活性蛋白特异性地递送至 巨噬细胞我们将利用这些材料来回答我们的第一个关键问题： 激活负责免疫细胞浸润的中枢神经系统（CNS）实质？我们 假设循环中单核细胞和中性粒细胞活化将诱导健康人中的中心浸润 小鼠，同时加剧炎症性疾病的浸润。我们将优化免疫调节的变化， 纳米凝胶激活循环先天免疫细胞的炎症（干扰素γ）与耐受性 （白细胞介素10）。我们将评估循环先天免疫细胞激活的程度， 纳米凝胶影响细胞在健康小鼠和炎症性疾病小鼠模型中的生物分布。 第二种技术是一种可注射的水凝胶，其包封细胞因子和供体巨噬细胞， 用于脑内植入。通过直接注射免疫调节蛋白和骨髓细胞到 我们将评估浸润性髓样细胞表型对健康小鼠脑实质的影响， 小胶质细胞与任何激活或从外周浸润分开。我们将量化 植入脑实质内的经典极化巨噬细胞与交替极化巨噬细胞激活脑- 常驻小胶质细胞趋向炎症并诱导神经功能缺陷（即功能性、解剖性）。作为证据 概念，我们将评估抗炎细胞因子和巨噬细胞作为预防性的局部递送 治疗与LPS攻击相关的炎性脑损伤。MIRA奖将允许PI （克莱格）承诺更多的时间和资源，这些悬而未决的问题，跨学科合作， 培训和指导多元化的科学工作队伍。我们预计，在这条线的长期投资， 调查将导致对炎症引起的脑损伤机制的基本见解，以及 用于特定疾病适应症的转化技术。