Glycosomes are essential, parasite-specific organelles found in kinetoplastids, the causative agents of diseases affecting more than 70 million people globally. Currently, there is a fundamental gap in the knowledge of the mechanisms that regulate glycosome biology. The long-term goal is to identify the mechanisms involved in the maintenance, biogenesis and remodeling of glycosomes in the kinetoplastid Trypanosoma brucei. The central hypothesis is that glycosomes form de novo through the formation of pre- glycosomal vesicles that mature through a sequential process of protein import and predict that glycosome protein content changes during the maturation process and in response to environmental conditions. The short-term goal of this proposal is to characterize the molecular mechanisms that affect glycosome maturation and remodeling. The rationale for this project is that understanding the mechanisms that regulate glycosome biology will reveal attractive new drug targets. In pursuit of these goals, we will carry out the following specific aims: 1) Identify the post-translational modifications of the glycosome protein, TbPEX11, in different glycosome populations, 2) Identify the pathways that regulate glycosome remodeling in response to changes in environmental conditions 3) Identify glucose-dependent changes in glycosome protein expression and transcriptome response to extracellular glucose. This work is significant and will positively impact the field, as it will resolve mechanisms of glycosome biogenesis and elucidate processes that can be exploited for therapeutic design.
The proposed research is relevant to public health because the discovery of mechanisms which regulate glycosome maturation and remodeling will identify potential drug targets that may be exploited in the development of drugs to treat diseases caused by kinetoplastid parasites. Hence, the proposed research is relevant to the portion of the NIH's mission pertaining to the development of knowledge that will help reduce the burden of human disease.
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