Does peripheral localized chronic inflammation predispose to neurodegeneration?

描述(申请人提供)：这项研究计划的目的是调查局部的外周慢性炎症是否有助于神经炎症的发展，并最终导致体内的神经变性。为此，我们将在我们实验室最近建立的col1-IL1β-XAT转基因小鼠模型中应用体细胞嵌合体分析，该模型利用基于Cre/loxP的分子遗传学方法在时间和空间上激活含有休眠的IL-1β转录单位的种系传递的重组底物。通过组织病理学、免疫组织化学和行为学研究，初步数据表明，关节内注射Cre后，col1-IL1β-XAT转基因小鼠的膝关节和颞下颌关节发生了关节炎。对外周诱导的col1-IL1β-XAT转基因小鼠脑组织的分析显示，GFAP和MHC II类免疫细胞化学激活了星形胶质细胞和小胶质细胞，以及几个炎症相关基因的mRNA上调，包括小鼠IL-1、TNFpha、MHC-II、GFAP和COX-2。为了进一步开发和描述这一模型，提出了以下具体目标。(1)描述在年轻和老年col1-IL1β-XAT转基因小鼠诱导膝关节炎后，随着时间的推移，神经炎症的发展。(2)检测外周转基因激活对复合COL1-IL1β-XAT/3xTg-AD转基因小鼠脑病理的影响。这些研究将确定局部外周炎症和衰老是否是小鼠神经炎症和阿尔茨海默病病理发展的风险因素。虽然在这里用于阿尔茨海默病的初步研究，但col1-IL1beta-XAT小鼠可以立即应用于其他慢性神经退行性疾病的研究，如ALS、帕金森氏病和神经毒性疾病。最终，这个模型将有助于阐明IL-1在脑部炎症中的作用。这些信息对于我们理解抗炎治疗在AD和其他疾病中的益处至关重要，并将指导靶向干预的合理应用和发展。

DESCRIPTION (provided by applicant): The purpose of this research proposal is to investigate whether localized peripheral chronic inflammation contributes to the development of neuroinflammation and ultimately neurodegeneration in vivo. To this end, we will employ somatic mosaic analysis in the Col1-IL1beta-XAT transgenic mouse model recently developed in our laboratory, which utilizes a Cre/loxP based molecular genetic method to temporally and spatially activate a germline-transmitted recombinational substrate containing a dormant IL-1beta transcription unit. Preliminary data demonstrate the development of arthritis in the knees and temporomandibular joints of Col1-IL1beta-XAT transgenic mice after intra-articular Cre administration as assessed by histopathological, immunohistochemical and behavioral studies. Analysis of brain tissue harvested from peripherally-induced Col1-IL1beta-XAT transgenic mice revealed astrocyte and microglia activation by GFAP and MHC class II immunocytochemistry, as well as mRNA upregulation of several inflammation-related genes, including murine IL-1, TNFalpha, MHC-II, GFAP and COX-2. The following specific aims are proposed to further develop and characterize this model. (1) Characterize the development of neuroinflammation following the induction of knee arthritis in young and old Col1-IL1beta-XAT transgenic mice over time. (2) Determine whether peripheral transgene activation impacts brain pathology in compound Col1-IL1beta-XAT/3xTg-AD transgenic mice. These studies will establish whether localized peripheral inflammation and aging are risk factors for the development of neuroinflammation and Alzheimer's disease pathology in mice. Although used here for a pilot investigation of Alzheimer's disease, the Col1-IL1beta-XAT mice can be immediately applied to studies of other chronic neurodegenerative conditions such as ALS, Parkinson's disease, and neurotoxic conditions. Ultimately, this model will contribute to the elucidation of the role of IL-1 in brain inflammation. Such information is critical to our understanding of the benefits of anti-inflammatory therapy in AD and other conditions and will guide the rational application and development of targeted interventions.