The peroxisome is a ubiquitous subcellular organelle and more than 60 proteins responsible for various cellular functions are known to be localized in peroxisomes. The importance of the functions of peroxisomes in cellular biology is underscored by the identification of 17 fatal inherited neurological disorders associated with their dysfunction. In addition to peroxisomal dysfunction in inherited disorders, studies from our laboratory report dysfunction of peroxisomes in inflammatory disease as a result of a decrease in the number of peroxisomes. Based on the importance of peroxisomes in normal cellular biology and related genetic diseases, we hypothesize that inflammatory disease events signal/trigger the process which alters the structure (proteins and lipids) and functions peroxisomes and thus compromises peroxisomal metabolic contribution to cells/tissue indicating a role for peroxisomal biology in the pathology of inflammatory neurological diseases. Secondly, these effects may vary in different cell types of the central nervous system (CNS). Therefore, the proposed studies are designed to investigate the structure/function of peroxisomes in different cell types of CNS and the mechanisms for their alterations under inflammatory conditions.
Specific aims are: 1. To determine the alterations in peroxisomes in different cell types of CNS and the mechanism of their alteration under inflammatory conditions and to investigate the mechanism responsible for these alterations. 2. To investigate the structural/functional alterations in peroxisomes by lipidomic and proteomic analysis of purified peroxisomes from different cell types of CNS. The proposed studies will utilize state of the art techniques in lipidomics and proteomics and will provide a better understanding of the structure and functions of peroxisomes in control tissue and will provide information regarding the role of peroxisomal dysfunction in the pathobiology of the neuroinflammatory disease process. ? ?
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