Deciphering the Relevance and Etiology of Th2 Cytokine Skewing in WASP KO Mice

破译 WASP KO 小鼠 Th2 细胞因子偏差的相关性和病因学

• 批准号: 7331050
• 负责人: Deanna D Nguyen
• 金额: $ 5.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7331050
• 关键词: Actins; Animal Model; Antigen-Presenting Cells; Cell Differentiation process; Cells; Chronic Disease; Colitis; Colon; DNA Sequence Rearrangement; Data; Defect; Dendritic Cells; Development; Disease; Elevation; Etiology; Event; Gastrointestinal tract structure; Genes; Genus Cola; Hematopoietic; Human; Immune; Immune response; Immune system; Infiltration; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-13; Interleukin-4; Intestines; Knock-out; Knockout Mice; Lamina Propria; Lead; Leukocytes; Lymphocyte; Lymphocyte Activation; Maintenance; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Pathogenesis; Patients; Peripheral; Phenotype; Play; Population; Proteins; Role; Signal Transduction; Signaling Molecule; Source; T-Lymphocyte; Wiskott-Aldrich Syndrome; animal data; cell motility; cell type; cytokine; human disease; macrophage; mortality; novel; novel therapeutics; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): The precise pathogenesis of inflammatory bowel disease (IBD) is unknown, but data from animal studies suggest a dysregulated immune response to intestinal flora. We aim to aid in the understanding of this human disease by closely examining the pathogenesis of a novel animal model of IBD, Wiskott-Aldrich Syndrome Protein (WASP) knockout (KO) mice. WASP, identified as the protein defective in patients with Wiskott-Aldrich Syndrome (WAS), is an intracellular signaling molecule expressed exclusively in hematopoietic cells and involved in actin cytoskeletal rearrangements. WASP KO mouse T cells, similar to T cells from WAS patients, harbor severe T cell signaling defects. In addition, WASP KO mice develop colitis, similar to 10% of WAS patients who suffer from an IBD-like disease. Preliminary studies have shown an infiltration of lymphocytes, macrophages, and dendritic cells into the lamina propria of the inflamed WASP KO mouse colons. This lamina propria infiltrate produces elevated levels of the Th2 cytokines IL-4 and IL-13. In this proposal, we aim to define the roles of Th1 and Th2 cytokines in the development of colitis in WASP KO mice. We will investigate the immediate cellular source of Th2 cytokines and the proximal aberrant cell population that eventual leads to Th2 cytokine induction. Lastly, we will investigate the molecular mechanisms underlying Th2 cytokine skewing by examining the expression of transcription factors known to be critical in T cell and NK-T cell differentiation. Determining the cell types and mechanisms underlying Th2 cytokine skewing may aid in our understanding of the pathogenesis of IBD and lead to new therapeutic targets of the disease. In summary, we will study mice lacking the Wiskott-Aldrich Syndrome protein, a molecule missing in patients with Wiskott-Aldrich Syndrome, as a new model of inflammatory bowel disease. Determining the mechanisms underlying disease pathogenesis in these mice, which models a human disease also associated with intestinal inflammation, will aid in our understanding of the abnormalities that cause inflammatory bowel disease in humans and will hopefully lead to new treatment ideas for the disease.

描述（由申请人提供）：炎症性肠病（IBD）的确切发病机制尚不清楚，但动物研究数据表明对肠道植物群的免疫反应失调。我们的目的是通过仔细研究IBD的新型动物模型Wiskott-Aldrich综合征蛋白（WASP）敲除（KO）小鼠的发病机制来帮助理解这种人类疾病。WASP被鉴定为Wiskott-Aldrich综合征（WAS）患者中的蛋白质缺陷，是仅在造血细胞中表达并参与肌动蛋白细胞骨架重排的细胞内信号分子。WASP KO小鼠T细胞，类似于来自WAS患者的T细胞，具有严重的T细胞信号传导缺陷。此外，WASP KO小鼠发生结肠炎，类似于10%患有IBD样疾病的WAS患者。初步研究显示淋巴细胞、巨噬细胞和树突状细胞浸润到发炎的WASP KO小鼠结肠的固有层中。这种固有层浸润产生升高水平的Th 2细胞因子IL-4和IL-13。在这个建议中，我们的目标是确定的作用，Th 1和Th 2细胞因子在结肠炎的发展WASP基因敲除小鼠。我们将研究直接的细胞来源的Th 2细胞因子和近端异常细胞群，最终导致Th 2细胞因子诱导。最后，我们将通过检测已知在T细胞和NK-T细胞分化中至关重要的转录因子的表达来研究Th 2细胞因子偏斜的分子机制。确定Th 2细胞因子偏移的细胞类型和机制可能有助于我们理解IBD的发病机制，并导致疾病的新的治疗靶点。总之，我们将研究缺乏Wiskott-Aldrich综合征蛋白（Wiskott-Aldrich综合征患者中缺失的分子）的小鼠作为炎症性肠病的新模型。确定这些小鼠中疾病发病机制的潜在机制，这些小鼠模拟了与肠道炎症相关的人类疾病，将有助于我们了解导致人类炎症性肠病的异常，并有望为该疾病带来新的治疗思路。