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.

项目摘要：患有创伤、自身免疫性疾病、病毒感染或长期 暴露在毒素中通常会造成急性脑损伤，导致脑部功能和解剖结构的改变。 大脑。科学家揭示了先天免疫细胞驱动急性脑损伤的两个关键机制 损伤：激活的中性粒细胞和单核细胞从体循环渗入脑实质， 以及脑内小胶质细胞的慢性激活。然而，在我们对基础科学的理解上存在着一条鸿沟 这些重叠的炎症过程，这使靶向治疗的发展复杂化。至 相对于渗入血液来源的髓系细胞，脑内驻留的小胶质细胞在多大程度上 炎症性疾病中急性脑损伤的责任？为了解决这一首要问题，我们 发明了两种使药物输送成为可能的技术。第一项技术是一种生物兼容和可生物降解的技术 纳米凝胶，由共价交联的丙烯酸单体组成，可将活性蛋白专门传递给 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：在多大程度上是外围的 激活导致免疫细胞渗入中枢神经系统(CNS)实质？我们 假设循环内单核细胞和中性粒细胞的激活将导致健康人的中枢渗透 小鼠，同时加剧炎症疾病的渗透。我们将优化免疫调节变种 纳米凝胶激活循环中的天然免疫细胞走向炎症(干扰素-γ)与耐受性 (白介素10)。我们将评估循环中的天然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，它包裹了合适的细胞因子和供体巨噬细胞。 用于脑内植入。通过将免疫调节蛋白和髓系细胞直接注射到 我们将评估浸润性髓系细胞表型对脑内滞留的影响。 小胶质细胞独立于周围的任何激活或渗透。我们将量化在何种程度上 传统和交替极化的巨噬细胞，植入脑实质，激活大脑- 驻留的小胶质细胞导致炎症并导致神经功能障碍(即功能、解剖学上的)。作为证据- 概念，我们将评估局部递送抗炎细胞因子和巨噬细胞作为预防 治疗与脂多糖挑战相关的炎症性脑损伤。米拉奖将允许少年派 (克莱格)将更多的时间和资源投入到这些悬而未决的问题上，跨学科合作， 培训和指导一支多元化的科学队伍。我们预计在这一领域的长期投资 研究将导致对炎症诱导的脑损伤机制的基本见解以及 针对特定疾病适应症的翻译技术。