Regulating Leukocyte Migration in Inflammation

我们研究计划的总体目标是了解白细胞如何迁移到 从而可以开发新的治疗策略来治疗炎症 疾病炎症的基本过程之一是细胞的定向迁移。 在趋化因子或病原体产物的梯度作用下，白细胞进入靶器官， 叫做趋化性。单独阻断趋化性对治疗人类炎症有效 疾病然而，白细胞如何感知和遵循化学梯度还没有很好的理解。 本申请的灵感来自于我们最近的发现，即TIPE（肿瘤细胞）中白细胞缺陷。 坏死因子-A-诱导蛋白8样）蛋白家族是“无罗盘的”， 可极化的：它们不能向化学引诱物迁移或进入神经系统。 组织引起炎症，尽管他们的正常运动。TIPE家族是“专业”的 磷脂第二信使PIP 2和PIP 3的转运蛋白，以及两者的危险因素 炎症和癌症。我们最初从小鼠脊髓中克隆了TIPE 2基因， 自身免疫性脑脊髓炎，并发现它优先由白细胞表达。我们 然后产生TIPE 2缺陷小鼠，并发现它们对神经系统的免疫反应有显著的抵抗力。 炎症出乎意料的是，TIPE 2缺陷型白细胞在运动性或活化方面没有缺陷， 但是在它们的方向性上严重受损，即，感知和跟随梯度的能力 化学引诱物。因此，我们建议TIPE系列是长期以来寻求的指南针 在炎症过程中赋予极性和方向性的白细胞。在本提案中，我们将 测试TIPE蛋白（i）在治疗期间引导白细胞进入神经组织的假设。 炎症和（ii）通过局部兴奋和全局机制抑制白细胞 抑制作用

The overall objective of our research program is to understand how leukocytes migrate into inflamed tissues so that new therapeutic strategies can be developed to treat inflammatory diseases. One of the fundamental processes of inflammation is the directed migration of leukocytes into target organs following a gradient of chemokines or pathogen products, a process called chemotaxis. Blocking chemotaxis alone is effective for treating human inflammatory diseases. However, how leukocytes sense and follow chemical gradients is not well understood. This application is inspired by our recent discovery that leukocytes deficient in the TIPE (tumor necrosis factor-a-induced protein 8-like) family of proteins are “compassless”, and non- polarizable: they are unable to polarize or migrate towards chemoattractants or into nervous tissue to cause inflammation despite their normal motility. The TIPE family are “professional” transfer proteins of the phospholipid second messengers PIP2 and PIP3, and risk factors for both inflammation and cancer. We initially cloned the TIPE2 gene from the spinal cord of mice with autoimmune encephalomyelitis and found that it was preferentially expressed by leukocytes. We then generated TIPE2-deficient mice and found that they were significantly resistant to neural inflammation. Unexpectedly, TIPE2-deficient leukocytes have no defects in motility or activation, but are severely compromised in their directionality, i.e., the ability to sense and follow the gradient of chemoattractants. We therefore propose that the TIPE family is the long-sought-after compass of leukocytes that confers polarity and directionality during inflammation. In this proposal, we will test the hypotheses that TIPE proteins (i) direct leukocytes into nervous tissue during inflammation and (ii) polarize leukocytes through the mechanism of local excitation and global inhibition.