Regulation of the Innate Response by the NGF-TrkA Receptor

Richard J. Ulevitch

The Scripps Research Institute

Funded in December, 2001: $300000 for 3 years


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Regulation of the Innate Response by the NGF-TrkA Receptor

Neuroimmune interactions play a decisive role over neuronal cell survival and cell death during neuronal injury, oxidative, and free radical stress. The importance of the innate immune system in response to neuronal injury has been recognized, and macrophage derived factors such as IL-1 have been identified as inducers of the synthesis of neurotrophic factors and their receptors (NGF, TrkA, p75NGFR). Our recent and unanticipated discovery of interactions of TLR2 with NGF and TrkA adds a new dimension to the importance of neurotrophic signaling under conditions of nerve injury. Now it appears that TrkA mediates survival of macrophages through the interaction with TLR2. At the same time NGF acting at neuronal TrkA receptors promotes survival and acting at p75NGFR promotes apoptosis of neurons.

Here we propose to examine the molecular mechanisms of the TrkA mediated interaction with TLR2 and determine how this protein tyrosine kinase receptor promotes macrophage survival. In relevant animal models, we will also examine the significance of TLR2 signaling and its modification by NGF on neuronal survival in acute nerve injury, where macrophages are thought to play an important role, and in diabetic neuropathy, where macrophages are thought to play a more moderate role.