Neurotrophins play key regulatory roles in cellular processes that are required for proper development and maintenance of the nervous system, such as cell survival/death, axon growth/guidance, and synaptic transmission/plasticity. Both Trk receptors and p75 participate in mediating these diverse neurotrophin actions, but p75 is mainly responsible for neurotrophin-dependent cell death at specific stages during development or under pathological conditions in the adult. The overall goal of this project is to understand the signaling mechanisms that underlie NGF's action regarding cell death and survival, with a focus on Rac and Rho, which are regulated by p75. P75 activates Rac in a prolonged manner that correlates with apoptosis, while co-activation of Trk/p75 leads to transient Rac activation and cell survival. These results suggest that the kinetics of Rac activation may be the key determinant in cellular outcome between cell survival and death. Regulation of Rho, on the other hand, may be determined by which coreceptor that p75 associates with: With neurotrophins/Trk, p75 inhibits Rho, while it activates Rho as a co-receptor for the Nogo receptor, NgR. P75 is often induced by injury in the adult nervous system and its expression in such cases has been linked to apoptosis. After the experimental injuries that induced p75 and cell death, Rho was activated, suggesting that controlling Rho activation by p75 will be critical in preventing cell death and degeneration after injuries. Our overall hypothesis is therefore that regulation of Rac and Rho by p75 determines the outcome between cell death and survival/regeneration. In an effort to understand the mechanisms by which p75 activates Rac and Rho, we discovered that the Kalirin family of guanidine exchange factors (GEF), Kalirin7 and 9, bind p75. Kalirin7 contains a Rac GEF domain, while Kalirin9 contains both Rac and Rho GEF domains.
The specific aims i nclude: (1) To determine the mechanisms of transient Rac activation by Kalirin7, (2) To determine whether prolonged Rac activation is necessary for apoptosis, and (3) To determine whether Kalirin9 is responsible for regulating the opposite's action of p75 for Rho activity both in vitro and in vivo after spinal cord injury. The outcome of this study will result in significant advancement of the current knowledge of NGF signaling, by elucidating the basic biochemical mechanisms behind the complex interplay between p75 and Trk, as well as p75 and NgR. A detailed understanding of the mechanisms may ultimately prompt therapeutic strategies for promoting regeneration and limiting degeneration in cases of neuronal injury and disease. ? ?
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