Does peripheral localized chronic inflammation predispose to neurodegeneration?

外周局部慢性炎症是否容易导致神经退行性变？

• 批准号: 7783400
• 负责人: Stephanos Kyrkanides
• 金额: $ 3.14万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7783400
• 关键词: Address; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyotrophic Lateral Sclerosis; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Astrocytes; Behavioral; Brain; Brain Pathology; Breeding; Cells; Chronic; Chronic Childhood Arthritis; Collagen; Complementary DNA; Condition; Coupled; Data; Degenerative Disorder; Deposition; Development; Disease; Encephalitis; Epidemiologic Studies; Evaluation; Excision; Family Felidae; Functional disorder; Galactosidase; Genes; Genetic Polymorphism; Genetic Recombination; Genetic Transcription; Glial Fibrillary Acidic Protein; Goals; Green Fluorescent Proteins; Histology; Human; Immunologic Deficiency Syndromes; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-1; International; Intervention; Intra-Articular Injections; Investigation; Joints; Knee; Knockout Mice; Laboratories; Link; Lip structure; Localized; MHC Class II Genes; Messenger RNA; Meta-Analysis; Methods; Microglia; Modeling; Molecular; Molecular Genetics; Mus; Myasthenia Gravis; Nerve Degeneration; PTGS2 gene; Pain; Parkinson Disease; Pathology; Periodontitis; Peripheral; Principal Investigator; Purpose; Recombinants; Reporter Genes; Research Proposals; Risk Factors; Role; Saline; Somatic Gene Therapy; Technology; Temporomandibular Joint; Time; Tissue Harvesting; Transgenes; Transgenic Mice; Transgenic Organisms; Up-Regulation; Viral; Viral Vector; Week; base; brain tissue; immunocytochemistry; in vivo; interest; mouse model; neuroinflammation; neurotoxic; programs; promoter; recombinase; research study; tau phosphorylation

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.

描述（由申请人提供）：本研究提案的目的是研究局部外周慢性炎症是否有助于体内神经炎症和最终神经变性的发展。为此，我们将在我们实验室最近开发的Col 1-IL-1 β-XAT转基因小鼠模型中采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IL-1 β转录单位的种系传递重组底物。初步数据表明，通过组织病理学、免疫组织化学和行为学研究评估，关节内Cre给药后Col 1-IL 1 β-XAT转基因小鼠膝关节和颞下颌关节中关节炎的发展。从外周诱导的Col 1-IL 1 β-XAT转基因小鼠中采集的脑组织分析显示，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，以及几种炎症相关基因（包括鼠IL-1、TNF α、MHC-II、GFAP和考克斯-2）的mRNA上调。提出了以下具体目标，以进一步发展和描述这一模式。(1)描述幼年和老年Col 1-IL 1 β-XAT转基因小鼠诱导膝关节炎后神经炎症随时间的发展。(2)确定外周转基因激活是否影响化合物Col 1-IL 1 β-XAT/3xTg-AD转基因小鼠的脑病理学。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学发展的危险因素。虽然在这里用于阿尔茨海默病的初步研究，但Col 1-IL 1 β-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，帕金森病和神经毒性疾病。最终，该模型将有助于阐明IL-1在脑炎症中的作用。这些信息对于我们了解抗炎治疗对AD和其他疾病的益处至关重要，并将指导靶向干预措施的合理应用和开发。

项目成果

Osteoarthritis accelerates and exacerbates Alzheimer's disease pathology in mice.

• DOI: 10.1186/1742-2094-8-112
• 发表时间: 2011-09-07
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Kyrkanides S;Tallents RH;Miller JN;Olschowka ME;Johnson R;Yang M;Olschowka JA;Brouxhon SM;O'Banion MK
• 通讯作者: O'Banion MK