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High-probability grants
According to our matching algorithm, Amanda Smith is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2002 — 2003 |
Smith, Amanda D |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Stress Stimulated Peptides in Forced Use Neuroprotection @ University of Pittsburgh At Pittsburgh
DESCRIPTION (provided by applicant): Forced use of the impaired forelimb in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of Parkinson's disease, ameliorates behavioral asymmetry and restores dopamine (DA) content in the striatum when commenced immediately after neurotoxic insult. However, the mechanism by which forced-limb use improves behavioral and neurochemical functioning is unknown. Although forced impaired limb use has positive effects on the compromised brain, it can be regarded as a form of restraint stress. Thus, like other stressful stimuli, we might predict that casting the forelimb of animals will stimulate the hypothalamic-pituitary-adrenal axis (HPA axis). Stimulation of the HPA axis results in the release of peptides (e.g. corticotrophin-releasing) into the portal bloodstream where they are transported to the anterior and intermediate lobe of the pituitary stimulating the release of several peptides derived from pro-opiornelanocortin [e.g. adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (alpha, beta and gamma-MSH) and ACTH4-10]. ACTH stimulates the adrenal cortex to release corticosterone (CORT). My preliminary data indicates that unilateral forelimb casting produces an increase in circulating CORT levels and GDNF and BDNF protein levels in the striatum. Thus, I propose to explore one aspect of the manner in which an exercise-trophic-factor-neuroprotection link might occur. Specifically, I will examine the impact of forced exercise on peptides whose release can be initiated through stimulation of the HPA axis. I will focus on ACTH related peptides (i.e., ?-MSH and CORT). Although these peptides and the associated HPA axis are most commonly associated with stress and are usually thought of as being toxic, I will outline evidence that in fact activation of the HPA axis can also serve a critical neuroprotective function and that a better understanding of this function may lead to novel and important strategies for the treatment of PD Thus, the overall goal of the present proposal is to examine the impact of forced forelimb use on peptides whose release can be initiated through activation of the HPA axis and their role in forced limb use-induced protection. To achieve this goal I propose 2 specific aims: (1) determine the impact of forced limb use on CORT levels and whether there is a causal relationship between CORT levels, neurotrophic factor expression, and forced use-induced neuroprotection in a 6-OHDA rodent model of PD and (2) determine the relationship between forced limb use-induced neuroprotection and the increased expression of specific melanocortins. A better understanding of the mechanism by which exercise protects against 6-OHDA neurotoxicity holds great promise to provide insights into the development of such therapies, including offering a rational basis for physical therapy and targets of drug discovery.
|
0.958 |
2004 — 2008 |
Smith, Amanda D |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Endogenous Neuroprotective Agents in Parkinson's Disease @ University of Pittsburgh At Pittsburgh
DESCRIPTION (provided by applicant): 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.
|
0.958 |