Modulating the Proteasome in Inflammatory Bowel Disease

描述（由申请人提供）：炎症性肠病被认为是由遗传易感宿主对共生肠道微生物的不适当免疫反应引起的。先天免疫系统对微生物的异常感知触发致病性T淋巴细胞的发育，从而引发和传播肠道炎症。我们之前的研究表明，T淋巴细胞对微生物病原体的反应似乎经历了不对称分裂，产生了两个不同命运的子细胞（Chang等人，Science 2007）。我们最近还提供了一种新的不对称分裂机制的证据，即蛋白酶体的不对称定位，以及有丝分裂期间靶向破坏因子的不平等降解，导致子细胞的关键命运决定因素的不平等分裂（Chang等人，免疫，出版中）。我们实验室使用结肠炎过继性转移模型的初步证据表明，CD4+ T细胞可能在对共生肠道微生物的失调免疫反应中进行不对称分裂。在本提案中，我们将：(1)确定蛋白酶体的不对称分离是否在对共生微生物进行失调免疫反应的CD4+ T细胞分裂中明显；(2)确定抑制蛋白酶体活性是否会破坏CD4+ T细胞引起肠道炎症的能力。实现这一提议的目标可能会对调节炎症性肠病发病机制的新机制产生重要的见解，并可能确定针对治疗的新途径。

DESCRIPTION (provided by applicant): Inflammatory bowel disease is believed to result from an inappropriate immune response to commensal intestinal microbes in a genetically susceptible host. Aberrant sensing of microbes by the innate immune system triggers the development of pathogenic T lymphocytes that initiate and propagate intestinal inflammation. We have previously shown that a T lymphocyte responding against a microbial pathogen appears to undergo asymmetric division to give rise to two differentially fated daughter cells (Chang et al., Science 2007). We have also recently provided evidence for a novel mechanism of asymmetric division whereby asymmetric localization of the proteasome, and consequently unequal degradation of factors targeted for destruction during mitosis, yields unequal partitioning of a key fate determinant to daughter cells (Chang et al., Immunity, in press). Preliminary evidence from our laboratory using an adoptive transfer model of colitis suggests that CD4+ T cells may undergo asymmetric division during a dysregulated immune response to commensal intestinal microbes. In this proposal, we will: (1) determine whether asymmetric segregation of the proteasome is evident in dividing CD4+ T cells undergoing a dysregulated immune response to commensal microbes; and (2) determine whether inhibition of proteasome activity disrupts the ability of CD4+ T cells to cause intestinal inflammation. Accomplishment of the aims of this proposal may yield important insights into a novel mechanism that may regulate the pathogenesis of inflammatory bowel disease, and may identify a new pathway against which therapies could be directed.