Macrophage-Activating MicroRNAs In the Pathogenesis of Leishmaniasis

巨噬细胞激活 MicroRNA 在利什曼病发病机制中的作用

• 批准号: 8397521
• 负责人: Mary E Wilson
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397521
• 关键词: Address; Afghanistan; Aftercare; American; Antiviral Agents; Attention; B-Lymphocytes; Cells; Cessation of life; Characteristics; Communicable Diseases; Cutaneous Leishmaniasis; Diagnosis; Disease; Environment; Epidemic; Freedom; Future; Gene Expression; Gene Silencing; Genes; Goals; Growth; Human; Human Genome; Hybrids; Immune; Immune system; Immunity; Infection; Interferons; Interleukin-12; International Agencies; Invaded; Iraq; Kuwait; Laboratories; Leishmania; Leishmania leishmania; Leishmaniasis; Length; Macrophage Activation; Mediating; MicroRNAs; Microbe; Middle East; Military Personnel; Mus; Organism; Oxygen; Paralysed; Parasites; Pathogenesis; Pathway interactions; Pattern; Phagocytosis; Phenotype; Protozoa; RNA Sequences; Role; Signal Pathway; Soldier; Stimulus; System; T-Lymphocyte; Therapeutic Agents; Toxic effect; Transcript; Untranslated RNA; Visceral Leishmaniasis; World War II; carcinogenesis; cell type; cytokine; experience; innovation; interest; killings; macrophage; microbial; microbicide; obligate intracellular parasite; operation; overexpression; prevent; programs; response

The Leishmania spp. protozoa have a profound effect on the host cell that they invade. These parasites reside intracellularly usually in macrophages, a cell type with the capacity to kill intracellular microbes. Rather than succumb, Leishmania paralyze the microbicidal pathways of the host cell, changing the macrophage from a lethal cell to an intracellular safe haven which allows the parasite to survive, replicate and ultimately spread to neighboring cells. The mechanism(s) through which the parasite "paralyzes" the host microbicidal function is incompletely understood. It has recently come to light that most eukaryotic organisms utilize short noncoding RNA sequences to globally regulate expression of a wide variety of genes. Indeed short RNA sequences of 18-30 bp in length, called microRNAs, are critical for regulating expression of an estimated 30% of the human genome. The hypothesis underlying this proposal is that microRNAs are the upstream trigger(s) determining which pattern of macrophage activation will occur after Leishmania infection. We will address the following questions. (1) What microRNAs does the parasite usually induce or suppress during infection of macrophages? (2) Which microRNAs are induced in response to stimuli that activate macrophage toward different polar phenotypes? (3) Is there overlap between the microRNAs discovered in Aims 1 and 2, and what is the effect of experimental manipulation of these microRNAs on Leishmania-infected macrophages? Specific aims of the proposal are: 1. To perform a global profiling of changes in microRNA expression induced in response to phagocytosis of L. chagasi by human macrophages. 2. To use a similar profiling approach to determine which microRNAs are induced in response to macrophage activation toward different polarized phenotypes. Of primary interest will be the microRNA changes that occur during M1 (classical) activation with reciprocal changes in other forms of macrophage activation, since classically activated macrophages can kill intracellular Leishmania. 3. To correlate the results of Aims 1 and 2, and to selectively either overexpress or suppress macrophage expression of selected microRNAs that may change in the pattern of macrophage activation or intracellular parasite growth.

利什曼原虫属。原生动物对其入侵的宿主细胞具有深远的影响。这些 寄生虫通常存在于细胞内巨噬细胞中，巨噬细胞是一种具有杀死细胞内寄生虫能力的细胞类型 微生物。利什曼原虫并没有屈服，而是瘫痪了宿主细胞的杀菌途径， 将巨噬细胞从致命细胞转变为细胞内的避风港，使寄生虫能够 存活、复制并最终扩散到邻近细胞。机制 寄生虫“麻痹”宿主的杀菌功能尚不完全清楚。 最近发现大多数真核生物利用短非编码 RNA 全局调节多种基因表达的序列。确实很短的RNA序列 长度为 18-30 bp，称为 microRNA，对于调节估计 30% 的表达至关重要 人类基因组。这一提议的假设是 microRNA 是 上游触发器确定之后将发生哪种巨噬细胞激活模式 利什曼原虫感染。我们将解答以下问题。 (1) 哪些 microRNA 具有以下作用： 寄生虫在感染巨噬细胞时通常诱导或抑制？ (2) 哪些 microRNA 是 响应激活巨噬细胞朝向不同极性表型的刺激而诱导？ (3) 是 目标 1 和目标 2 中发现的 microRNA 之间存在重叠，其效果如何 在利什曼原虫感染的巨噬细胞上对这些 microRNA 进行实验操作？具体目标 该提案的内容是： 1. 对响应引起的 microRNA 表达变化进行全局分析 人类巨噬细胞对恰加西乳杆菌的吞噬作用。 2. 使用类似的分析方法来确定哪些 microRNA 被诱导响应 巨噬细胞针对不同极化表型的激活。主要兴趣将是 M1（经典）激活过程中发生的 microRNA 变化以及其他变化的相互变化 巨噬细胞激活的形式，因为经典激活的巨噬细胞可以杀死细胞内的 利什曼原虫。 3. 将目标 1 和 2 的结果关联起来，并选择性地过度表达或抑制 选定的 microRNA 的巨噬细胞表达可能会改变巨噬细胞的模式 激活或细胞内寄生虫生长。