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.