Investigating post Transcriptional Essential Gene Regulation In Leishmania (InTEGRL)

利什曼原虫是导致利什曼病的原因，利什曼病是第九大传染病负担。近50%的患者是儿童。目前还没有疫苗，流行病的发生率和严重程度都在增加。治疗有毒性和痛苦的副作用，不适合儿童，并有越来越多的阻力发展。单细胞利什曼原虫在其生命周期中转变为许多不同的形式，以适应不同的宿主;从哺乳动物到白蛉，再通过白蛉叮咬回到哺乳动物。只有某些生命周期阶段形式的利什曼原虫细胞才能感染人类并存活。寄生虫的外观，代谢和毒力蛋白的主要变化发生在这些过渡期间，使它们能够生存。利什曼原虫基因表达几乎完全依赖于mRNA调控。为了应对环境的变化，特定的寄生虫蛋白质结合mRNA并靶向它们产生蛋白质，以指导和促进适应。控制这些寄生虫变化的蛋白质使它们能够适应，在人类中生存并感染人类。这些蛋白质是利什曼原虫感染的毒力和传播所必需的。通过表征这些调节蛋白及其下游靶点，我们可以发现利什曼原虫使用什么机制来控制它们的生命周期变化。如果我们能分离并阻止控制面板“调节器”蛋白，我们就能阻止利什曼原虫在人类中感染。利什曼原虫蛋白质与人类蛋白质不同，因此我们可以利用这些差异来靶向利什曼原虫特异性发育调节因子，阻断其功能并阻断寄生虫的入侵能力。最近，Walrad实验室不仅确定了与利什曼原虫基因结合的全套蛋白质，而且从中发现了12种对细胞存活和感染至关重要的关键利什曼原虫调节蛋白。这些调节剂中的大多数是病原体特异性的，并且不存在于动物中，使得这些潜在的可药用靶标。我们现在想知道这些调节因子是如何发挥作用的;它们结合了哪些其他蛋白质和RNA，使利什曼原虫能够存活和感染。这些重要的调节因子或它们的辅因子可能会为阻止利什曼原虫感染的新药发现提供信息。

Leishmania are the cause of leishmaniasis, the 9th greatest infectious disease burden. Nearly 50% of all patients are children. No vaccine currently exists and epidemics are increasing in occurrence and severity. Treatments have toxic and painful side effects, are inappropriate for children and have growing resistances developing. The single-cell Leishmania transforms into many different forms during its lifecycle to adapt to very different hosts; moving from mammals to sandflies and back to mammals by sandfly bites. Only Leishmania cells of certain lifecycle stage forms can infect and survive in humans. Major changes to the parasite's appearance, metabolism and virulence proteins occur during these transitions that enable them to survive. Leishmania gene expression relies almost exclusively upon mRNA regulation. In response to changes in the environment, specific parasite proteins bind mRNAs and target them for protein production to guide and promote adaptation. Proteins that control the changes these parasites go through enable them to adapt, survive in and infect humans. Such proteins are essential for the virulence and spread of Leishmania infection. By characterising such regulatory proteins and their downstream targets, we can find out what mechanisms Leishmania use to control their lifecycle changes. If we can isolate and stop control panel "Regulator" proteins, we can block Leishmania from establishing an infection in humans. Significant findings would provide insight to leishmaniasis research and related diseases.Leishmania proteins are different from human proteins; therefore we can exploit these differences to target Leishmania-specific developmental regulators, block their function and block the parasites' ability to invade. Recently, the Walrad lab has not only identified the full sets of proteins that bind genes in Leishmania, but from these have found 12 key Leishmania regulator proteins that are essential for cellular survival and infection. The majority of these regulators are pathogen-specific and not present in animals, making these potential druggable targets. We want to find out now how these regulators function; what other proteins and RNAs they bind to enable Leishmania to survive and infect. It is possible these essential Regulators or their cofactors could inform new drug discovery to block Leishmania infection.