Fatty Alcohol Synthesis and Virulence in Leishmania

利什曼原虫的脂肪醇合成和毒力

• 批准号: 9244051
• 负责人: RACHEL ZUFFEREY
• 金额: $ 12.38万
• 依托单位: ST. JOHN'S UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244051
• 关键词: Acyl Coenzyme A; Acyltransferase; Anabolism; Animal Diseases; Antibodies; Antiparasitic Agents; Biochemistry; Biogenesis; Biological Assay; Biology; Biomedical Research; Cell physiology; Cell surface; Cellular biology; Clinical Research; Clinical Trials; Complement; Data; Development; Drug Design; Environment; Enzymes; Esters; Ethers; Fatty Acids; Fatty Alcohols; GPI Membrane Anchors; Generations; Genetic; Glycerol; Goals; Growth; Human; Immunofluorescence Immunologic; In Vitro; Infection; Intervention; Knowledge; Laboratories; Lead; Learning; Leishmania; Leishmaniasis; Life Cycle Stages; Lipid Biochemistry; Lipids; Mastigophora; Membrane; Metabolic; Miltefosine; Molecular Biology; Mus; Orthologous Gene; Oxidoreductase; Parasites; Parasitic Diseases; Pathogenesis; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacology; Phospholipid Ethers; Play; Positioning Attribute; Process; Production; Property; Public Health; Research; Role; Route; Sand Flies; Structure; Students; Techniques; Testing; Universities; Vertebral column; Virulence; Virulence Factors; Yeasts; base; fighting; human disease; in vivo; interdisciplinary approach; lipid biosynthesis; lipid metabolism; lipophosphonoglycan; macrophage; mutant; novel; novel strategies; pathogen; prevent; public health relevance; vector

 DESCRIPTION (provided by applicant): Leishmania species are protozoan parasites that cause important human diseases in the tropics and subtropics worldwide and, thus, represent a major public health problem. Ether lipids are important constituents of Leishmania membranes, and more importantly, are structural components of various virulence factors, such as the very abundant cell surface lipophosphoglycan and the glycosylphosphatidylinositol(GPI)-anchored protease GP63. Both play crucial roles during the entire life cycle of the parasite. Ether lipid-based drugs such as miltefosine, currently used in clinical trials, inhibit parasite growth in vitr and in vivo, and are likely to interfere with the ether lipid biosynthetic pathway. This supports te idea that this metabolic route can be targeted for further drug design. Our previous studies have established that the first two enzymes of the ether lipid biosynthetic pathway in L. major, dihydroxyacetonephosphate acyltransferase LmDAT and alkyl dihydroxyacetonephosphate synthase LmADS, are implicated in the synthesis of the virulence factor lipophosphoglycan and cellular ether lipids, which play a crucial role in parasite pathogenesis. Our preliminary results have suggested that i) LmFAR is involved in the production of fatty alcohols which are essential for the synthesis of ether lipids, and ii) LmFAR is important for growth of the parasite. This proposal will test the central hypothesis that Leishmania peroxisomal fatty acyl-CoA reductase LmFAR is essential for ether lipid metabolism and generation of the virulence factor lipophosphoglycan, and consequently, for pathogenesis. To test this hypothesis, we propose to use two Specific Aims that combine a multidisciplinary approach that involves molecular biology, genetics, biochemistry, and cell biology techniques. In Specific Aim 1, we will investigate the enzymatic properties of LmFAR and its subcellular localization. In Specific Aim 2, we will assess the importance of LmFAR in ether lipid biosynthesis, virulence, and sensitivity to ether lipid-based drugs. Understanding the function of LmFAR is important for the development of novel strategies to prevent and treat Leishmania infections. In addition, this project will enhance the research environment at St. John's University by providing underprivileged students with numerous opportunities to learn the fundamentals of biomedical research.

 描述（由申请人提供）：利什曼原虫属原生动物寄生虫，在全世界热带和亚热带地区引起重要的人类疾病，因此代表了主要的公共卫生问题。醚脂是利什曼原虫膜的重要组成部分，更重要的是，它是各种毒力因子的结构成分，例如非常丰富的细胞表面脂磷酸聚糖和糖基磷脂酰肌醇（GPI）锚定蛋白酶GP63。两者在寄生虫的整个生命周期中都发挥着至关重要的作用。目前用于临床试验的醚类脂质药物如米替福辛，可抑制体外和体内寄生虫的生长，并可能干扰醚类脂质生物合成途径。这支持了这样的观点：这种代谢途径可以作为进一步药物设计的目标。我们之前的研究已经证实，L. Major中醚脂质生物合成途径的前两种酶，二羟丙酮磷酸酰基转移酶LmDAT和烷基二羟丙酮磷酸合酶LmADS，参与毒力因子脂磷酸聚糖和细胞醚脂质的合成，在毒力因子脂磷酸聚糖和细胞醚脂质的合成中发挥着重要作用。 在寄生虫发病机制中发挥重要作用。我们的初步结果表明，i) LmFAR 参与脂肪醇的产生，脂肪醇对于醚脂的合成至关重要，ii) LmFAR 对于寄生虫的生长很重要。该提案将检验以下中心假设：利什曼原虫过氧化物酶体脂肪酰基辅酶 A 还原酶 LmFAR 对于醚脂代谢和毒力因子脂磷酸聚糖的生成至关重要，因此对于发病机制至关重要。为了检验这一假设，我们建议使用两个具体目标，结合涉及分子生物学、遗传学、生物化学和细胞生物学技术的多学科方法。在具体目标 1 中，我们将研究 LmFAR 的酶特性及其亚细胞定位。在具体目标 2 中，我们将评估 LmFAR 在醚脂生物合成、毒力和对醚脂类药物的敏感性中的重要性。了解 LmFAR 的功能对于制定预防和治疗利什曼原虫感染的新策略非常重要。此外，该项目还将为贫困学生提供大量学习生物医学研究基础知识的机会，从而改善圣约翰大学的研究环境。