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

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，对肠道菌群的免疫反应失调。我们的目标是通过仔细研究一种新的IBD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是一种细胞内信号分子，仅在造血细胞中表达，参与肌动蛋白细胞骨架重排，被认为是Wiskott-Aldrich综合征（WAS）患者的缺陷蛋白。WASP KO小鼠T细胞与WAS患者的T细胞相似，具有严重的T细胞信号缺陷。此外，WASP KO小鼠出现结肠炎，类似于10%患有ibd样疾病的WAS患者。初步研究表明，淋巴细胞、巨噬细胞和树突状细胞浸润到炎症的WASP KO小鼠结肠固有层。这种固有层浸润产生Th2细胞因子IL-4和IL-13水平升高。在本提案中，我们旨在确定Th1和Th2细胞因子在WASP KO小鼠结肠炎发展中的作用。我们将研究Th2细胞因子的直接细胞来源和最终导致Th2细胞因子诱导的近端异常细胞群。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Th2细胞因子偏斜的分子机制。确定Th2细胞因子偏斜的细胞类型和机制可能有助于我们了解IBD的发病机制，并导致疾病的新治疗靶点。总之，我们将研究缺乏Wiskott-Aldrich综合征蛋白的小鼠，这是Wiskott-Aldrich综合征患者缺失的一种分子，作为炎症性肠病的新模型。确定这些小鼠的潜在疾病发病机制，从而模拟与肠道炎症相关的人类疾病，将有助于我们理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。

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.