My career goal is to form an independent research group to invest in training the next generation of scientists through addressing how the malaria parasite prepares for vector/host transmission. My training in both structural biology and parasitology has uniquely positioned me to use both approaches to address important questions about the malaria parasite. Receipt of this K22 award will greatly aid in accomplishing the vital tasks required to establish a research group, and would provide the funding and time necessary to amass the foundational data and publications necessary to become competitive for R01 research support. Plasmodium parasites cause 300-500 million malarial infections and nearly a million deaths annually. Infection by the parasite requires the transmission between a mosquito vector and vertebrate host, and vice versa., Targeting these transmission processes has been the focus of many therapeutic interventions, such as through vaccines and antibody blocking strategies. Recent work has demonstrated that the parasite uses translational repression of specific mRNAs during both of these transmission points, and that disrupting this process severely decreases or completely abrogates parasite infectivity. My previous and current studies focus upon the mechanisms of silencing and protecting mRNAs through the formation of RNA storage granules in the sporozoite form of the parasite that are passed from mosquitoes to mice. Building upon these studies, this research proposal will test aspects of the specific hypothesis that proper formation of RNA storage granules at the vector/host transition is crucial for infectivity of the malaria parasite. In order to accomplish this, I propose to investigate: (1) The Role of RNA-Binding Proteins in the Formation of RNA Storage Granules by using reverse genetics and biochemical approaches to dissect the Puf2 protein and other protein/RNA interactions identified by IP/MS, RNAseq or candidate approaches;and (2) The Structure/Function of Storage Granule Components through high-resolution structural and biochemical investigations both with and without their binding partners. By successfully addressing these aims, further research questions will no doubt arise that will further focus our understanding of the mechanisms of these interactions. Taken together, these findings will highlight key parasite-specific features that can be exploited for new therapeutic treatments or preventative measures. . NARRATIVE Malaria is a major global health burden, infecting 300-500 million people and causing 800,000 deaths each year. This research will investigate the formation of protein/RNA complexes that are critical for the infectivity of the parasite as it is passed from a mosquito to a mouse. Understanding these processes will help us to understand disease transmission, and may provide new means to disrupt it.
Malaria is a major global health burden, infecting 300-500 million people and causing 800,000 deaths each year. This research will investigate the formation of protein/RNA complexes that are critical for the infectivity of the parasite as it is passed from a mosquito to a mouse. Understanding these processes will help us to understand disease transmission, and may provide new means to disrupt it.
|Zander, Ryan A; Vijay, Rahul; Pack, Angela D et al. (2017) Th1-like Plasmodium-Specific Memory CD4+ T Cells Support Humoral Immunity. Cell Rep 21:1839-1852|
|Muñoz, Elyse E; Hart, Kevin J; Walker, Michael P et al. (2017) ALBA4 modulates its stage-specific interactions and specific mRNA fates during Plasmodium yoelii growth and transmission. Mol Microbiol 106:266-284|
|El-Manzalawy, Yasser; Munoz, Elyse E; Lindner, Scott E et al. (2016) PlasmoSEP: Predicting surface-exposed proteins on the malaria parasite using semisupervised self-training and expert-annotated data. Proteomics 16:2967-2976|
|Reddy, B P Niranjan; Shrestha, Sony; Hart, Kevin J et al. (2015) A bioinformatic survey of RNA-binding proteins in Plasmodium. BMC Genomics 16:890|
|Lindner, Scott E; Mikolajczak, Sebastian A; Vaughan, Ashley M et al. (2013) Perturbations of Plasmodium Puf2 expression and RNA-seq of Puf2-deficient sporozoites reveal a critical role in maintaining RNA homeostasis and parasite transmissibility. Cell Microbiol 15:1266-83|