Targeting Entry Pathways in Leishmaniasis

描述（由申请人提供）：候选人/培训：我的目标是获得必要的培训，成为利什曼原虫感染分子发病机制的独立研究者。我是一名儿科传染病研究员，获得了微生物学博士学位，研究弓形虫寄生虫。在我的研究期间，我开始研究巨噬细胞摄取利什曼原虫的调节机制。我的博士学位为我提供了微生物学和细胞生物学方面的经验，我在研究员培训期间积累了小鼠发病机制模型的经验。我现在计划在生物化学和药理学方面发展更多的专业知识和指导研究经验，并将其与利什曼病的发病机制和治疗联系起来。我的导师是一位研究肌动蛋白聚合调节机制的生物化学家。指导我的还有一位寄生虫学家，他在利什曼原虫感染及其通过小鼠免疫系统的调节方面有着丰富的经验，一位研究整合素激活机制的细胞生物学家，以及一位药理学家。我之前的研究背景，我的临床训练，我在奖学金期间的研究，以及我在K08奖励期间的指导研究和课程的结合，将增强我的科学知识广度，使我能够为分子寄生虫学领域做出独特的贡献。

DESCRIPTION (provided by applicant): CANDIDATE/TRAINING: My goal for this career award is to obtain the necessary training to become an independent investigator in the molecular pathogenesis of Leishmania infection. I am a pediatric infectious diseases fellow who earned a Ph.D. in microbiology studying the parasite Toxoplasma gondii. During my fellowship, I began to study the mechanisms that regulate the uptake of Leishmania by macrophages. My Ph.D. provided me with experience in microbiology and cell biology, and I developed experience with mouse models of pathogenesis during my fellowship training. I now plan to develop additional expertise and mentored research experience in biochemistry and pharmacology, and relate it to the pathogenesis and treatment of leishmaniasis. My mentor is a biochemist who studies the mechanisms that regulate actin polymerization. I will also be mentored by a parasitologist with extensive experience in Leishmania infection and its regulation by the mouse immune system, a cell biologist who works on the mechanisms of integrin activation, and a pharmacologist. The combination of my previous research background, my clinical training, my research during my fellowship, and my mentored research and coursework during the K08 award period will enhance my scientific breadth of knowledge, and uniquely enable me to contribute to the field of molecular parasitology. PROJECT: Leishmania is a parasite that causes cutaneous or visceral disease. Current therapies have significant side effects, and parasites are developing resistance to them, so new therapies are needed. Leishmania must live inside phagocytes to survive. Both life cycle stages, promastigotes and amastigotes, infect macrophages. Studying how Leishmania is engulfed by macrophages will help us understand its pathogenesis and could define new antiparasitic targets. My work shows that Abl family kinases permit uptake of Leishmania by macrophages, and that inhibiting these kinases ameliorates leishmaniasis in mice. This project further defines the mechanism by which Leishmania is engulfed by macrophages and causes disease, with the eventual goal that drugs that inhibit uptake will provide novel therapeutic strategies. I hypothesize 1) interactions between �2 integrin and Abl allow promastigote uptake by macrophages, 2) interactions among FcR, Src family kinases, and Arg allow amastigote uptake by macrophages, and 3) drugs that can inhibit these signaling proteins will decrease the manifestations of cutaneous leishmaniasis in mice. In Specific Aim 1, I will characterize the �2 integrin:Abl interaction and its role during promastigote uptake by macrophages. In Specific Aim 2, I will determine how Src family kinases affect amastigote uptake by macrophages and the severity of cutaneous leishmaniasis in mice. In Specific Aim 3, I will assess whether inhibitors of parasite uptake by macrophages, alone or in combination with miltefosine, decrease the severity of cutaneous leishmaniasis in mice. My studies will elucidate the initial steps of parasit uptake, improve our understanding of the pathogenesis of leishmaniasis, and provide novel approaches to treat this devastating infection.