Peripheral nerve trauma is associated with a variety of well documented morphological and physiological alterations. Wallerian degeneration, removal and recycling of axonal and myelin debris. Schwann cell proliferation, protein synthesis/phosphorylation, and axonal regeneration all occur following peripheral nerve trauma. The underlying signal transduction mechanisms involved in peripheral nerve regeneration are poorly understood. A better understanding of these signal transduction cascades is necessary to improve therapeutic intervention in nerve regeneration. Numerous studies implicate protein kinase C (PKC) in neurite outgrowth. However, a thorough assessment of the specific isoforms involved in nerve regeneration has not been conducted. The long term goal of this project are to better clarify the role of the specific isoforms of PKC, alpha, epsilon, and zeta in nerve regeneration in regards to specific target proteins and down-stream signal transduction cascades, in order to meet these goals, I am proposing to undertake the following project objectives: I. Characterize the presence and location of protein kinase C (PKC) isoforms alpha, epsilon, and zeta in normal rat sciatic nerve. II. Determine the effect of sciatic nerve crush injury on the subcellular distribution of PKC isoforms alpha, epsilon, and zeta, proximal and distal to the site of injury, at days 1, 7, and 35 post-trauma. III. Examine the effect of various compounds which stimulate or inhibit PKC alpha, epsilon, and zeta activity on the in vitro protein phosphorylation patterns in the proximal and distal nerve segment on days 1, 7, and 35 following sciatic nerve crush injury and utilize this information to establish potential target proteins phosphorylated by these PKC isoforms. IV. Examine the involvement of 3 subfamilies of mitogen activated protein kinases (MAPK) in the nerve regenerative process proximal and distal to the site of injury, at days 1, 7, and 35 post-trauma-p44/p42 MAPK, stress- activated kinase SAPK/JNK, and P38 MAPK. In vitro studies will be conducted to assess the role of PKC alpha, epsilon, and zeta in altering the levels and phosphorylation patterns of these MAPK in sciatic nerve.
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