The present application describes the research and career plan laid out for my development into an independent, productive, and well funded investigator in the area of the neurobiology of neurodegenerative disease. The research plan that is proposed investigates the role of circulating insulin like growth factor (IGF-1) and associated proteins in protection of the nigrostriatal dopamine (DA) pathway against oxidative stress induced by 6-hydroxydopamine (6-OHDA) and the nature of this protection. The loss of DA neurons in this pathway underlies the motor dysfunctions observed in patients with Parkinson's disease (PD). Forced use of the impaired forelimb for 7 days in a unilateral 6-OHDA lesion model of Parkinson's disease, ameliorates behavioral asymmetry and restores DA content in the striatum when commenced immediately after or prior to neurotoxic insult. The mechanism by which forced use protects against 6-OHDA toxicity is unknown. Moreover, whether forced use protects the nigrostriatal pathway from degenerating, rescue cells in danger of degenerating in the absence of intervention, or promotes sprouting, is not known. Physical exercise by treadmill or running wheel has been shown to increase the brain uptake of IGF-1 from the circulation and this IGF-1 has been shown to mediate exercise-induced increases in neurogenesis and brain derived neurotrophic factor mRNA in the hippocampus. Thus, it may be surmised that forced use protection is mediated via increases in brain IGF-1 subsequent to increases in circulating IGF-1. Our preliminary data using Fluoro-jade B as a marker of degeneration suggests that forced limb use prevents the nigrostriatal pathway from degenerating. Further, a preliminary screen of altered genes after 6-OHDA and 6-OHDA +/- forced limb use, with microarray analysis suggests that IGF-1 may be involved. In the present proposal, we will: 1) Further examine the impact of forced use/disuse on the anatomical and functional state of DA neurons using behavior, biochemistry and histological analyses; 2) investigate the role of IGF-1 in forced limb use-induced protection, whether this effect can be mimicked by systemic administration of IGF-1 and whether subsequent up-regulation of other trophic factor signaling (i.e. GDNF and BDNF) is involved; and 3) examine whether the protective effects of forced limb use and IGF-1 are mediated via activation of the pro-survival phosphatidylinositol 3-kinase (PI 3K)/Akt and extracellular signal-regulated kinase (ERK) signaling cascades. The career development plan in the present proposal focuses on providing me with the technical skills needed to accomplish the Aims outlined in the present proposal. Further, it will provide the skills and discipline needed to increase my visibility in the greater neuroscience community. This will be accomplished through formal training and practical experience in the areas of public speaking, writing and networking. The mentors that are described herein will actively participate in this undertaking and will further mediate increasing the network of neuroscientists in which I interact locally and nationally.
