PLURIPOTENCY OF NOVEL TICK CYSTEINE PROTEASE INHIBITORS DURING HEMATOPHAGY

新型蜱半胱氨酸蛋白酶抑制剂在吸血过程中的多能性

基本信息

批准号：
10515240
负责人：
SARAH E MORGAN
金额：
$ 44.4万
依托单位：
UNIVERSITY OF SOUTHERN MISSISSIPPI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10515240
关键词：
Address Amblyomma Animal Model Antibody titer measurement Binding Black-legged Tick Blood Cavia Complex Mixtures Cystatins Cysteine Proteinase Inhibitors Data Development Devices Diagnostic tests Double-Stranded RNA Early Diagnosis Environment Event Family Gene Expression Gene Silencing Genes Goals Host Defense Mechanism Hydrogels Immune Immune response Immunity Immunologics Immunomodulators Impairment Infection Inflammatory Intake Ixodidae Knowledge Life Cycle Stages Lipopolysaccharides Mediator of activation protein Molecular Outcome Pathology Phase Phenotype Prevalence Prevention Preventive measure Preventive vaccine Protein Family Proteins Public Health RNA Interference Reagent Recombinant Proteins Recombinants Regulation Rickettsia Infections Rickettsia parkeri Role Saliva Salivary Salivary Glands Site System Systems Biology Testing Therapeutic Tick-Borne Diseases Ticks Treatment Efficacy Vaccinated Vaccination Vaccines Work antibiotic tolerance combat efficacy testing experience experimental study feeding guinea pig model hematophagy immunogenicity immunoregulation improved in vivo Model insight novel pathogen pre-clinical response saliva secretion side effect spotted fever success therapy design tick feeding tick saliva tick transmission tick-borne tool transcriptomics transmission process vaccine trial vector vector competence vector tick

Address Amblyomma Animal Model Antibody titer measurement Binding Black-legged Tick Blood Cavia Complex Mixtures Cystatins Cysteine Proteinase Inhibitors Data Development Devices Diagnostic tests Double-Stranded RNA Early Diagnosis Environment Event Family Gene Expression Gene Silencing Genes Goals Host Defense Mechanism Hydrogels Immune Immune response Immunity Immunologics Immunomodulators Impairment Infection Inflammatory Intake Ixodidae Knowledge Life Cycle Stages Lipopolysaccharides Mediator of activation protein Molecular Outcome Pathology Phase Phenotype Prevalence Prevention Preventive measure Preventive vaccine Protein Family Proteins Public Health RNA Interference Reagent Recombinant Proteins Recombinants Regulation Rickettsia Infections Rickettsia parkeri Role Saliva Salivary Salivary Glands Site System Systems Biology Testing Therapeutic Tick-Borne Diseases Ticks Treatment Efficacy Vaccinated Vaccination Vaccines Work antibiotic tolerance combat efficacy testing experience experimental study feeding guinea pig model hematophagy immunogenicity immunoregulation improved in vivo Model insight novel pathogen pre-clinical response saliva secretion side effect spotted fever success therapy design tick feeding tick saliva tick transmission tick-borne tool transcriptomics transmission process vaccine trial vector vector competence vector tick

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项目摘要

Project Summary Ixodid ticks blood feed for several days to weeks on their hosts. Hematophagy is assisted by tick’s saliva, which is repeatedly injected into the host skin, alternating with blood intake. Tick saliva contains a mixture of bioactive molecules that target a broad spectrum of host defense mechanisms to allow the tick to blood feed on the vertebrate host for several days, many of which are host immunomodulators. Understanding the molecular interactions between tick vectors, vertebrate hosts, and pathogens is critical in developing strategies to combat ticks and tick-borne diseases. This proposal explores a fundamental mechanism of tick hematophagy success, mainly regulating vertebrate host proteolytic cascades at sites of tick feeding (skin) by multiple cysteine protease inhibitors of the cystatin family. We hypothesize that three novel Amblyomma maculatum cystatins modulate the vertebrate host immune response during blood-feeding. We will test the hypothesis by pursuing the following specific aims: 1) To complete the detailed functional characterization of three novel recombinant Amblyomma maculatum salivary cystatins as candidate host immunomodulators, 2) To investigate the role of each of the three A. maculatum salivary cystatin genes in tick feeding and pathogen transmission success by conditional knock- downs in ticks (RNAi) and, 3) To test the potential of artificially boosting the host humoral response against these three A. maculatum cystatins by vaccine studies in a preclinical animal model, with an ultimate goal that the achieved boost in the host antibody titers against tick cystatins will block their action at the tick-host interface and may impair tick feeding and/or pathogen transmission success. For Aim 2, we will also evaluate the use of bio-inspired hydrogels as non-invasive, transcuticular dsRNA delivery devices that could provide a commercially scalable approach for the delivery of these therapies to ticks in their natural environment. These aims will provide critical reagents, tools, and data to address the crucial gap in the fundamental knowledge of the role of redundancy of host immunomodulators in tick saliva.

项目摘要 ixodid在宿主上滴答了几天到几周的血液。血肿得到了tick的辅助唾液反复注入宿主皮肤，随着血液摄入而改变。滴答唾液包含针对广泛宿主防御的生物活性分子的混合物几天是宿主免疫调节剂。了解tick矢量之间的分子相互作用，脊椎动物的宿主和病原体对于制定战略与tick虫和tick传播至关重要疾病。该提案探讨了tick肿瘤成功的基本机制，主要是通过多个半胱氨酸调节脊椎动物宿主蛋白水解级联抑制蛋白家族的蛋白酶抑制剂。我们假设这三个新颖的Amblyomma Maculatum 半胱氨酸蛋白酶调节血液喂养过程中脊椎动物宿主免疫反应。我们将测试通过追求以下特定目的来假设：1）完成详细的功能三种新型重组amblyomma maculatum唾液囊蛋白的表征为候选宿主免疫调节剂，2）研究三个曲霉中的每一个的作用有条件敲门的滴答喂养和病原体传播成功中的唾液胱抑素基因 tick滴（RNAi）和3）测试人为增强宿主体液反应的潜力通过临床前动物模型中的疫苗研究，针对这三个伴曲霉的囊肿。在宿主抗体滴答中，针对tick cystatins实现的最终目标将阻止他们在tick-host界面的动作，可能会损害滴答滴答的进食和/或病原体传播成功。对于AIM 2，我们还将评估生物启发的水凝胶的使用无创，跨越DSRNA的递送设备，可以提供商业上可扩展的方法将这些疗法传递给其自然环境中的滴答作用。这些目标将提供关键试剂，工具和数据，以解决基本知识的关键差距 tick唾液中宿主免疫调节剂的冗余。