MOLECULAR GENETICS OF LEISHMANIA

利什曼原虫的分子遗传学

• 批准号: 7758218
• 负责人: Stephen M Beverley
• 金额: $ 65.71万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-03-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758218
• 关键词: Acquired Immunodeficiency Syndrome; Adopted; Algorithms; Autophagocytosis; Back; Biological; Cell Volumes; Chromates; Chromatin; Chromatin Structure; Communities; Country; DNA-Directed RNA Polymerase; Dactinomycin; Data; Databases; Detection; Development; Diploidy; Down-Regulation; Eukaryota; Evolution; Gene Cluster; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genome; Genomics; Global Change; Goals; Grant; Homologous Gene; Image; In Vitro; Infection; Label; Leishmania; Leishmania major; Leishmaniasis; Lesion; Link; Maps; Mediating; Metabolic Pathway; Methodology; Methods; Middle East; Molecular; Molecular Genetics; Molecular Profiling; Mutagenesis; Nature; Nutrient; Oligonucleotide Microarrays; Opportunistic Infections; Oxidants; Parasites; Pathway interactions; Patients; Pattern; Persons; Physical condensation; Play; Polyribosomes; Process; RNA Interference; RNA Stability; Relative (related person); Research; Research Personnel; Resources; Role; Sand Flies; Spottings; Staging; Stimulus; Structure; Surveys; Temperature; Testing; Thiouracil; Time; Translations; Tropical Disease; Virulence; antimicrobial peptide; asexual; base; comparative genomic hybridization; expression vector; functional genomics; genetic analysis; genetic manipulation; genome-wide; improved; in vivo; knockout gene; mRNA Stability; metacyclogenesis; mutant; parasite genome; positional cloning; programs; response; success; tool; vector

Parasites of the trypanosomatid protozoan genus Leishmania are responsible for a spectrum of tropical diseases that afflict more than 10 million people worldwide, and depending on the specific speciesand mmune status of the infected person, can be severe or fatal. In several countries, leishmaniasis is a common opportunistic infection in AIDS patients, and many USsolidiers stationed in the Middle East have been infected. The goal of our research is to develop and apply new methods for the identification of genes used by this parasite to carry out its infectious cycle. Our premise is that the availability of powerful molecular genetic tools, and identification of genes important to parasite virulence, will radically advance our ability to develop improved control strategies. In previous studies methods were developed for manipulating the parasite genome in a variety ofways by forward or reverse genetics, and to develop functional genomic approaches such as transposon mutagenesis and expression profiling. Success with expression profiling now enables us to incorporate this powerful methodology more comprehensively into our research program, and undertake a broader survey of patterns and mechanisms of gene expression in Leishmania, making use of both genetic and biological methodological advances from the prior grant period. The goal is to identify genes showing patterns of expression suggestive of functional roles in the infectious cycle, for example stage-specific expression or alterations in response to relevant stimuli, whose predictions and implications can then be tested experimentally. One example that will be pursued involves a new perspective on the differentiation of the parasite into the infectious metacyclic form transmitted by sand flies, involving global changes in parasite gene expression probably mediated by changes in chromating structure, specific changes in expression arising from a combination of mechanisms, and biological changes involving massive cellular remodeling and 'shrinkage' possibly mediated by autophagy.

锥虫原生动物利什曼原虫属的寄生虫造成了一系列热带病 困扰全球超过 1000 万人的疾病，具体取决于具体物种和 感染者的免疫状况可能很严重或致命。在一些国家，利什曼病是一种 艾滋病患者中常见的机会性感染，许多驻中东的美国士兵 被感染。我们研究的目标是开发和应用新的基因识别方法 被这种寄生虫用来执行其感染周期。我们的前提是拥有强大的 分子遗传学工具以及对寄生虫毒力重要的基因的鉴定将从根本上推进我们的研究 开发改进控制策略的能力。 在之前的研究中，开发了以多种方式操纵寄生虫基因组的方法 通过正向或反向遗传学，并开发功能基因组方法，例如转座子 诱变和表达谱。表达谱分析的成功现在使我们能够将其纳入 更全面地融入我们的研究计划中，并进行更广泛的调查 利什曼原虫基因表达模式和机制，利用遗传和生物学 与上一个资助期相比方法上的进步。目标是识别显示模式的基因 暗示感染周期中功能作用的表达，例如阶段特异性表达或 对相关刺激做出反应的改变，然后可以测试其预测和影响 实验性地。将要探讨的一个例子涉及一种关于差异化的新视角。 寄生虫进入由白蛉传播的传染性后循环形式，涉及寄生虫的整体变化 基因表达可能由染色结构的变化介导，表达的特定变化 由多种机制和涉及大规模细胞重塑的生物变化相结合而产生 和“收缩”可能是由自噬介导的。