Newton001 Biochemical Investigation of the Enzyme PRMT7 Function in Leishmania spp Parasite Infectivity; Screening Targets for Leishmaniasis Relevance

利什曼病是传染病中第九大疾病负担，是仅次于疟疾的第二大寄生虫病杀手，威胁着世界十分之一的人口。世卫组织估计，皮肤利什曼病每年新增70万至120万例，内脏利什曼病感染20万至40万人，其中10%至20%死亡。巴西受到这种疾病的所有病理影响，每年有3万新感染病例。超过70%的利什曼病患者年龄在15岁以下。目前还没有疫苗，而且对可用的治疗方法的抵抗力越来越强；这些治疗方法昂贵、剧毒，不适合儿童。在过去的十年里，随着疾病的严重程度的提高和领土的扩大，流行病有所增加。尽管迫切需要干预，但利什曼病仍然是一种被忽视的热带疾病。这在很大程度上是因为它折磨着社会上最贫穷的人。了解利什曼原虫中涉及的蛋白质的功能和活性。寄生虫的毒力将为抗击利什曼病的新的潜在方法提供有用的见解。在昆虫媒介和人类宿主之间传播的过程中，寄生虫适应环境的急剧变化。发育变化需要利什曼原虫细胞解释不断变化的环境线索，并协调快速的生存反应。特定生命周期的适应使寄生虫能够在宿主之间传播，并使寄生虫感染和疾病永久化。环境线索触发信号级联以启动发育事件。表达的“响应”蛋白使细胞能够适应特定的环境。在这些信号的下游，特定的RNA结合蛋白(RBPs)结合细胞反应所必需的mRNAs，并将其作为蛋白质生产、储存或降解的靶标。精确的基因调控协调细胞适应所必需的特定阶段蛋白的表达。通过这种方式，基因调控促进了寄生虫的存活和传染性。协调这些寄生虫对不同宿主细胞的适应并促进寄生虫感染的分子调控因子，对于我们更广泛地了解这种疾病至关重要。酶PRMT7是利什曼原虫毒力的一种新的调节因子。我们寻求结合我们的专业知识和设施来对PRMT7的功能进行生化表征，并探索它及其目标蛋白如何使寄生虫具有感染性。Cruz和Walrad实验室在利什曼原虫分子细胞生物学和转录组学方面拥有互补的专业知识和目标。克鲁兹实验室在利什曼原虫的分子特征方面有着广泛的历史。寄生虫。Walrad实验室在鉴定使寄生虫在宿主之间传播的RNA结合调节蛋白方面具有专业知识。我们的合作将对蛋白质精氨酸甲基转移酶PRMT7的功能、其蛋白质靶标以及这一途径如何参与利什曼原虫进行生化表征。传染性。PrMT7是第一个与宿主-寄生虫相互作用有关的利什曼原虫甲基化酶。初步证据表明，它可能通过修饰调节性RNA结合蛋白发挥作用。最近，MRC NIRG奖授予Walrad实验室关于涉及利什曼原虫的监管限制性商业惯例。寄生虫向人类感染形式的分化。

The Leishmaniases are the ninth largest disease burden amongst infectious diseases and the second biggest killer of parasitic diseases next to malaria, threatening one tenth of the world's population. WHO estimates 0.7-1.2 million new cases of cutaneous Leishmaniasis annually while visceral Leishmaniasis infects 200-400,000, killing 10-20% of them. Brazil is stricken by all pathologies of this disease with 30,000 new infections every year. Over 70% of leishmaniasis patients are under 15 years of age. No vaccine exists and there is a growing resistance to available treatments; which are expensive, highly toxic and unsuitable for children. The past decade has seen an increase of epidemics coincident with heightened severity of the disease and an expansion of territory. Despite the urgent need for intervention, leishmaniasis remains a neglected tropical disease. This is largely attributable to its afflicting the poorest of society. Understanding the function and activity of proteins implicated in Leishmania spp. parasite virulence will provide useful insight into new potential ways to combat Leishmaniasis.Leishmania spp. parasites adapt to drastic changes in environments during transmission between insect vectors and human hosts. Developmental changes require the Leishmania parasite cell to interpret changing environmental cues, and to coordinate a swift response for survival. Lifecycle-specific adaptions enable parasite transmission between hosts and perpetuate parasitic infections and diseases. Environmental cues trigger signalling cascades to initiate developmental events. Expressed 'response' proteins enable cellular adaptation to the given environment. Downstream of these signals, specific RNA binding proteins (RBPs) bind mRNAs essential for the cellular response and target them for protein production, storage or degradation. Precise gene regulation coordinates the expression of stage- specific proteins essential for cell adaptation. In this way gene regulation promotes parasite survival and infectivity.Molecular regulators that coordinate the adaptation of these parasites to different host cells and promote parasite infection are critically important to our broader understanding of this disease. The enzyme PRMT7 is a novel regulator of Leishmania virulence. We seek to combine our expertise and facilities to biochemically characterise PRMT7 function and explore how it and its target proteins enable parasite infectivity.The Cruz and Walrad laboratories have complementary expertise and objectives in Leishmania molecular cell biology and transcriptomics. The Cruz lab has an extensive history of molecular characterisation in Leishmania spp. parasites. The Walrad lab has expertise in characterising RNA binding regulatory proteins which enable parasite transmission between hosts.Our collaboration will biochemically characterise the function of the Protein aRginine Methyl Transferase enzyme, PRMT7, its protein targets and how this pathway participates in Leishmania spp. infectivity. PRMT7 is the first Leishmania methylating enzyme to be implicated in host-parasite interactions. Preliminary evidence suggests it may act via modification of regulatory RNA binding proteins, RBPs. The recent MRC NIRG award to the Walrad lab centres on regulatory RBPs involved in Leishmania spp. parasite differentiation to human infectious forms.