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

基本信息

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
项目类别：
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

项目摘要

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：因创伤性损伤，自身免疫性疾病，病毒感染或长时间造成的患者接触毒素通常会遭受急性脑损伤，从而导致功能和解剖变化大脑。科学家发现了两个关键机制，固有的免疫细胞驱动急性大脑损害：激活的嗜中性粒细胞和单核细胞从全身循环中浸润到脑实质中，和长期激活脑居民小胶质细胞。但是，我们的理解有基础科学的“差距” 在这些重叠的炎症过程中，这使靶向治疗的发展变得复杂。到大脑居民小胶质细胞多大，而不是浸润血液来源的髓样细胞负责炎症性疾病中的急性脑损伤？为了解决这个总体问题，我们发明了两种启用药物输送技术。第一种技术是一种可生物相容性且可生物降解的纳米凝胶由共价交联的丙烯酸单体组成，该单体专门提供活性蛋白巨噬细胞。我们将利用此材料回答我们的第一个关键问题：周边的程度在多大程度上负责中枢神经系统（CNS）副瘤免疫细胞浸润的激活？我们假设循环中的单核细胞和中性粒细胞激活将诱导健康中心浸润小鼠，同时加剧炎症性疾病的浸润。我们将优化的免疫调节变化纳米凝胶激活循环的先天免疫细胞朝着炎症（干扰素伽马）与耐受性激活（白介素10）。我们将评估使用靶向的循环先天免疫细胞激活的程度纳米凝胶会影响健康小鼠中细胞的生物分布和炎症性疾病的小鼠模型。第二种技术是封装细胞因子和供体巨噬细胞的可注射水凝胶，是合适的用于脑内植入。通过直接注射免疫调节蛋白和髓样细胞健康小鼠的实质，我们将评估浸润髓样细胞表型对脑居民的影响小胶质细胞与外围的任何激活或浸润中的任何激活分开。我们将量化经典与替代两极化的巨噬细胞，植入脑实质中，激活脑居民小胶质细胞炎症并诱导神经系统缺陷（即功能，解剖学）。作为证明概念，我们将评估抗炎细胞因子和巨噬细胞的局部递送作为预防性治疗与LPS挑战有关的炎症性脑损伤。 MIRA奖将允许PI （Clegg）将更多时间和资源用于这些未解决的问题，跨学科合作，培训和对多样化的科学劳动力的心理化。我们预计这一线的长期投资询问将导致对炎症引起的脑损伤机理的基本见解以及特定疾病适应症的翻译技术。