Targeting Entry Pathways in Leishmaniasis

瞄准利什曼病的进入途径

基本信息

批准号：
8588893
负责人：
Dawn Marie Wetzel
金额：
$ 4.24万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8588893
关键词：
Actins Adhesions Adverse effects Affect Antimony Antiparasitic Agents Award Binding Biochemical Biochemistry Biological Assay C3bi Cells Cellular biology Childhood Clinical Clinical Trials Communicable Diseases Complement Complement Receptor Cutaneous Cutaneous Leishmaniasis Data Defect Disease Doctor of Philosophy Energy Transfer Family Fc Receptor Fellowship Fibroblasts Genes Gleevec Goals Imatinib Immune system Immunoglobulin G Immunoglobulins Infection Integrin Binding Integrins Intervention Knowledge Laboratories Lead Leishmania Leishmaniasis Lesion Life Life Cycle Stages Macrophage-1 Antigen Mediating Membrane Mentors Microbiology Miltefosine Molecular Mus Parasites Parasitology Pathogenesis Pathway interactions Phagocytes Phagocytosis Pharmaceutical Preparations Pharmacology Phosphotransferases Process Protein Tyrosine Kinase Proteins Receptor Signaling Regulation Research Research Personnel Resistance development Role Sand Flies Severities Side Signaling Protein Skin Ulcer Staging Testing Therapeutic Toxoplasma gondii Training Visceral Work base cancer therapy career experience improved inhibitor/antagonist killings kinase inhibitor macrophage mouse model mutant novel novel strategies novel therapeutic intervention novel therapeutics overexpression polymerization receptor receptor binding src-Family Kinases treatment strategy uptake

项目摘要

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.

描述：候选人/训练是在Leishmania感染的分子发病机理中获得必要的训练和独立的训练。在微生物学和细胞生物学中，我在我的团契训练期间开发了发病机理的经验，并将其与利什曼病的发病机理和信任联系起来。由小鼠免疫系统对整合素的机制和药理学的结合，我的临床培训在我的临床培训中。有助于分子寄生虫学领域。项目：利什曼氏菌是对它们的抗性或内脏疾病，因此需要新的疗法。是英语并导致疾病，最终的目的是抑制抑制E的药物会提供新的治疗策略。 2整联蛋白并允许巨噬细胞，2）FCR之间的相互作用，SRC家族激酶噬菌体和3）可以在小鼠中抑制皮肤利什曼病的表现的信号蛋白。 2整联蛋白：巨噬细胞在特定目标中的抗抗激素摄取中的作用。巨噬细胞的寄生虫吸收，单独或与米尔特福修结合，降低了小鼠皮肤利什曼病的严重程度。感染。