Defining the Immunomodulatory Niche of Schistosoma haematobium IPSE

埃及血吸虫 IPSE 免疫调节生态位的定义

基本信息

批准号：
9107658
负责人：
Michael Harrison Hsieh
金额：
$ 47.12万
依托单位：
BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107658
关键词：
Achievement Address Adhesions Adopted Adult Affinity African Alleles Antibodies Binding Biochemical Biological Assay Bladder Cell Line Cell Nucleus Cells Chemotaxis Cloning Clustered Regularly Interspaced Short Palindromic Repeats Complementary DNA Consensus Sequence Cysteine Deposition Electrical Resistance Environment Enzyme-Linked Immunosorbent Assay Epithelial Epithelium Extracellular Matrix Fibroblasts Fibrosis Fluorescence Microscopy Gene Expression Genes Genetic Genetic Transcription Genitourinary system Genome Granuloma Health Helminths Homologous Gene Human IgE Immune Immune response Immunity Immunofluorescence Microscopy Immunoglobulin G Immunoglobulins In Vitro Individual Infection Infiltration Inflammatory Inflammatory Response Institution Interleukin-4 Intestines Kinetics Knowledge Liver Liver Fibrosis Location Malaria Malignant neoplasm of urinary bladder Measurement Measures Methods Modeling Molds Mus Nuclear Nuclear Protein Nuclear Translocation Parasites Pathology Pathway interactions Peptide Signal Sequences Population Property Protein Array Proteins Publishing RNA Interference Recombinants Research Research Personnel Reverse Transcriptase Polymerase Chain Reaction Risk Role Schistosoma Schistosoma haematobium Schistosoma hematobium infection Schistosoma mansoni Schistosoma mansonii infection Schistosomiasis Scientist Sequence Homologs Sister Specificity Surface Plasmon Resonance Testing Therapeutic Tight Junctions Time Tissue Survival Transgenic Organisms Urothelial Cell Urothelial Hyperplasia base chemokine cytokine disulfide bond economic impact egg electric impedance genetic manipulation genome editing glycosylation human morbidity human mortality immune clearance immunoregulation in vivo macrophage mouse model neglected tropical diseases novel novel therapeutics prevent research study socioeconomics success tool vector

项目摘要

DESCRIPTION (provided by applicant): Approximately 120 million individuals are infected with Schistosoma haematobium in sub-Saharan African alone. S. haematobium adult worms, the causative agent of urogenital schistosomiasis, lay eggs throughout the urogenital tract. These eggs induce a pronounced inflammatory response responsible for the human morbidity and mortality associated with infection. To date very little is known about how S. haematobium is able to induce such a robust immune response while evading immune clearance and immunity in many individuals. This lack of knowledge is due to the historical lack of both a model for S. haematobium egg- associated pathology, and genetic tools for manipulation of the S. haematobium parasite. Building on recent advances in the S. haematobium field, this collaborative proposal employs the first published mouse model of S. haematobium induced bladder pathology (generated by the PI), and the first successful approaches for genetic manipulation of S. haemtobium (pioneered by the co-investigators). The experiments proposed will explore the functions of the S. haematobium homolog of the parasite egg- secreted immunomodulatory protein IPSE. IPSE was originally described in S. mansoni, the sister species of schistosome responsible for hepatoenteric schistosomiasis. IPSE is the most abundant S. mansoni egg secreted protein, and has numerous published biochemical functions, many of which were first described by a co-investigator on this proposal. Our collaborative team across four institutions will first define the biochemical functions of the S. haematobium IPSE homologue. We will then generate genetically modified S. haematobium strains with deficient IPSE gene expression to determine the effects of IPSE in vivo. Achievement of the aims of this proposal would represent key milestones for S. haematobium research, including, to our knowledge, the first studies on S. haematobium-derived immunomodulatory proteins and the first use of transgenic S. haematobium strains to determine the function of an S. haematobium protein in vivo.

描述（由适用提供）：仅在撒哈拉以南非洲，大约有1.2亿人会感染血吸虫血吸虫病。泌尿生殖器血吸虫病的灾难性药物的止血链球菌成年蠕虫在整个泌尿生殖道中产卵。这些卵引起了导致与感染相关的人类发病率和死亡率的明显炎症反应。迄今为止，关于嗜血杆菌如何能够在许多个体中逃避免疫膜和免疫学的同时诱导这种强大的免疫冲源，知之甚少。缺乏知识是由于历史上缺乏与卵子链球菌相关的病理学的模型，也缺乏用于操纵寄生虫链球菌的遗传工具。该协作提案以最新进展为基础，采用了首个发表的hematobium S. haematobium诱导的小鼠模型（由PI生成），以及首次成功操纵S. haemtobium的成功方法（由共同投资者率先使用）。提出的实验将探索寄生虫分泌的免疫调节蛋白IPSE的止血链球菌同源物的功能。 IPSE最初是在曼森（S. IPSE是最丰富的Mansoni卵子分泌的蛋白质，并且具有许多发表的生化功能，其中许多功能首先是由共同评估者对此提案描述的。我们跨四个机构的合作团队将首先定义S. haematobium ipse同源物的生化功能。然后，我们将产生具有确定的IPSE基因表达的遗传修饰的止血链球菌菌株，以确定IPSE在体内的影响。该提案的目标的实现将代表链球菌研究的关键里程碑，包括，据我们所知，是对嗜血杆菌衍生的免疫调节蛋白的首次研究，以及首次使用转基因性嗜血杆菌菌株来确定hematobium菌株以确定hematobium蛋白在体内的功能。