Sexual Development of Cryptosporidium

隐孢子虫的性发育

• 批准号: 10538894
• 负责人: BORIS STRIEPEN
• 金额: $ 45.42万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-11-07 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538894
• 关键词: AIDS/HIV problem; Ablation; Acquired Immunodeficiency Syndrome; Apical; Atlases; Biological Assay; Cell Cycle Regulation; Cells; Cessation of life; Child; Child Health; Childhood; Chromosome Mapping; Cryo-electron tomography; Cryptosporidiosis; Cryptosporidium; Development; Diarrhea; Disease; Disease Outbreaks; Docking; Elements; Epigenetic Process; Event; Female; Fertilization; Flagella; Future; Gametogenesis; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic study; Genome; Germ Cells; Immunocompetent; Immunosuppression; Individual; Infant; Infection; Intestines; Life Cycle Stages; Link; Malignant Neoplasms; Malnutrition; Maps; Measures; Methods; Modeling; Molecular; Nutritional status; Opportunistic Infections; Organ Transplantation; Parasites; Patients; Pharmaceutical Preparations; Phase; Prevention; Process; Program Development; Prophylactic treatment; Proteins; Public Health; Reproduction spores; Resistance; Resolution; Risk Factors; Role; Rotavirus; Sexual Development; Specificity; Sporozoites; Structure; Subcellular structure; System; Technology; Testing; Vaccines; Water; asexual; chlorination; diarrheal disease; disease transmission; effective therapy; electron tomography; histone modification; imprint; insight; interest; intestinal epithelium; live cell imaging; loss of function; male; mortality; mutant; next generation; overexpression; pathogen; programs; sex; single cell sequencing; transcription factor; transmission process; waterborne illness

Project Abstract The protozoan parasite Cryptosporidium is one of the most important causes of severe diarrheal disease. In the U.S. this parasite is responsible for half of all waterborne disease outbreaks, some of which have occurred at massive scale. Patients suffering from immunosuppression due to HIV/AIDS, organ transplantation, or cancer are in gravest danger. The global public health impact is even larger: after Rotavirus, Cryptosporidium is the most important diarrheal pathogen in small children. In particular in the context of malnutrition, cryptosporidiosis has a highly significant imprint on childhood mortality. Cryptosporidiosis is also linked to stunting, thus leaving a lasting shadow on the future of children. This parasite has a single host life cycle, asexual and sexual processes occur sequentially in the intestinal epithelium of the same host. Completion of this developmental program is required for continued infection, severe disease, and transmission. We have built robust experimental systems to observe and manipulate the sexual development of Cryptosporidium and we unraveled key elements of the mechanisms that control the underlying gene expression systems. In this application we will define the epigenetic mechanisms that govern transition from asexual to sexual replication, we will unravel how the parasites choses between a male or female fate, and we will use emerging cyro-electron tomography and parasite genetics to understand how the unique ultrastructure of male gametes enables fertilization. The resulting findings will impact on our fundamental understanding of parasite development and on translational efforts to develop drugs and vaccines.

项目摘要 原生动物寄生虫隐孢子虫是严重腹泻的最重要原因之一 疾病。在美国，这种寄生虫造成了所有水传播疾病暴发的一半，有些是 其中发生在大规模。由于 艾滋病毒/艾滋病，器官移植或癌症处于最严重的危险中。全球公共卫生 撞击甚至更大：轮状病毒后，隐孢子虫是最重要的腹泻病原体 在小孩中。特别是在营养不良的背景下，隐孢子虫病具有高度 关于儿童死亡率的重大烙印。隐孢子虫病也与发育迟缓有关，因此 在儿童的未来留下持久的阴影。这个寄生虫有一个单一的宿主生命周期， 无性过程和性过程依次出现在同一宿主的肠上皮中。 持续感染，严重疾病，需要完成此发展计划 和传输。我们已经建立了强大的实验系统来观察和操纵 隐孢子虫的性发展，我们揭示了机制的关键要素 控制潜在的基因表达系统。在此应用中，我们将定义表观遗传学 管理从无性复制过渡到性复制的机制，我们将解开如何 寄生虫在男性或女性命运之间选择，我们将使用新兴的Cyro电子 断层扫描和寄生虫遗传学，以了解雄配子的独特超微结构如何 启用受精。由此产生的发现将影响我们对 寄生虫的发展以及开发药物和疫苗的转化努力。