Cryptosporidium parvum (C. parvum) is a category B priority pathogen that has the capacity to be weaponized. C. parvum is also an opportunistic pathogen of persons with acquired immunodeficiency syndrome (AIDS). C. parvum causes a severe and potentially life-threatening form of diarrhea for which there are currently no effective therapies. An analysis of the C. parvum genome indicates that there are a number of genes encoding unique C. parvum chromatin modifying enzymes, many of which have a unique domain architecture or are more closely related to plant, bacterial, and fungal orthologues than to their mammalian counterparts. These enzymes are hypothesized to be essential to the survival of the parasite and to function throughout the complex parasite life cycle to facilitate transcriptional regulation, DNA replication, recombination and repair. Thus, these enzymes represent excellent potential therapeutic targets for control of the C. parvum life cycle. The long-term objective is to develop basic information on novel C. parvum chromatin modifying enzymes to aid in rational drug design efforts to control this parasite. Currently, however, there is no information on the role of these enzymes in regulating the parasite life cycle, and no functional analyses of the enzymes encoded by these genes have been reported. Therefore, this exploratory proposal has the following specific aims: 1. Determine expression and sub-cellular distribution of 5 putative histone deacetylases during the early invasive life cycle of the parasite and correlate this expression with progression through the C. parvum life cycle. 2. Clone, heterologously express, and characterize the activities of recombinant versions of putative C. parvum histone deacetylase enzymes. 3. Test the efficacy of histone deacetylase inhibitors against C. parvum growth using an in vitro model of infection and correlate this with changes in C. parvum development. It is hoped that the results of this work will provide insight into the role of chromatin modifying enzymes in regulating the life cycle of Cryptosporidium parvum and perhaps other apicomplexans. Relevance to public health: Cryptosporidium parvum is a waterborne human parasite that has the capacity to be developed into a biological weapon and causes a potentially lethal form of diarrhea. There are currently no highly effective treatments for Cryptosporidium parvum. This research is a beginning step toward identifying novel methods to control this parasite. ? ? ?
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| Rider Jr, S D; Srinivasan, D G; Hilgarth, R S (2010) Chromatin-remodelling proteins of the pea aphid, Acyrthosiphon pisum (Harris). Insect Mol Biol 19 Suppl 2:201-14 |
| Rider Jr, Stanley Dean; Zhu, Guan (2010) Cryptosporidium: genomic and biochemical features. Exp Parasitol 124:2-9 |
| Rider Jr, S Dean; Zhu, Guan (2009) An apicomplexan ankyrin-repeat histone deacetylase with relatives in photosynthetic eukaryotes. Int J Parasitol 39:747-54 |
