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Molecular mayhem: Immune modulation and eicosanoid signaling during infection

分子混乱：感染期间的免疫调节和类二十烷酸信号传导

基本信息

批准号：
10667434
负责人：
Adler Ray Dillman
金额：
$ 37.77万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667434
关键词：
Affect Autoimmune Diseases Binding Biological Models Biology Celiac Disease Cells Crohn&apos s disease Drosophila genus Drosophila melanogaster Drug resistance Eicosanoids Evolution Fatty Acids Genetic Genetic Models Goals Health Human Immune response Immune signaling Immune system Immunity Immunosuppression In Vitro Infection Inflammatory Bowel Diseases Learning Lipids Mediating Modeling Molecular Morbidity - disease rate Natural Immunity Nematoda Nematode infections Outcome Parasites Parasitic nematode Pathology Pathway interactions Population Prevalence Protein Family Protein Secretion Proteins Research Research Project Grants Retinol Binding Proteins Signal Pathway Signal Transduction Source Tissues immunoregulation in silico in vivo member mortality novel novel therapeutic intervention recurrent infection small molecule success vaccination strategy

项目摘要

Project Summary/Abstract A central aspect of parasitic nematode success and prevalence is their ability to modify host biology, including evade and/or subvert the host’s immune response. In some cases, humans can host thousands of nematode parasites with little to no pathology, yet our understanding of this incredible evasion or suppression of the immune system remains limited. Modulation of host biology and the pathology they cause is largely effected through the release of proteins and small molecules that interact with host cells and tissues. There are hundreds of proteins released in nematode spit during an infection and only a few have been studied in any detail. My lab is focused on understanding host-parasite interactions, with an emphasis on elucidating the molecules that parasites release into the host, characterizing their interaction with host signaling pathways to modulate host biology, and learning from the evolution of the parasite arsenal how to manipulate the immune system. Over the next five years my lab will identify key genetic pathways in lipid-mediated immune signaling and identify molecular host- parasite interactions. Our specific focus will be to 1) establish experimental pipelines for identifying novel parasite-derived proteins and small molecules that modulate host biology, 2) determine the effects of the molecules we identify, beginning with members of the fatty acid- and retinol-binding (FAR) protein family, 3) elucidate molecular interactions between parasite molecules and host pathways, and 4) characterize eicosanoid signaling in Drosophila melanogaster, a genetic model of immunity. A major strategy of my lab's research is to combine in silico, in vitro, and in vivo experimental approaches with an established infection model that leverages our deep understanding of fruit fly biology and its powerful genetics, to reveal not only the binding targets of parasite proteins and molecules in an active infection, but also to define their effect on infection outcomes. Our overall goal is to understand how nematode parasites modify host biology in order to successfully infect them. This includes parasites’ ability to evade and/or suppress host immunity, which is important to human health in at least two ways. First, nematode infections continue to be a major source of global morbidity and mortality, affecting more than 25% of the world’s population. Increasing drug resistance and recurring infections compound this problem. And second, there is mounting evidence that the immunomodulatory effects of nematode infections can dampen or even eliminate the pathologies that define autoimmune disorders such as Crohn’s disease, inflammatory bowel disease, and Celiac disease. Understanding how nematodes suppress the immune system will lead to new treatment and vaccination strategies against nematode infection, and may reveal new avenues for treating autoimmune disorders. We will employ a powerful model system to probe immune modulation by nematodes to identify specific secreted proteins and small molecules as well as the signaling pathways they target to effectively manipulate host immunity.

项目总结/摘要寄生线虫成功和流行的一个中心方面是它们改变宿主生物学的能力，包括逃避和/或破坏宿主的免疫反应在某些情况下，人类可以寄生数千条线虫寄生虫几乎没有病理，但我们对这种令人难以置信的逃避或抑制免疫的理解，系统仍然有限。宿主生物学的调节及其引起的病理学主要通过释放与宿主细胞和组织相互作用的蛋白质和小分子。有数百种蛋白质在感染过程中释放在线虫的唾液中，只有少数被详细研究过。我的实验室专注于了解宿主-寄生虫相互作用，重点是阐明寄生虫的分子释放到宿主中，表征它们与宿主信号传导途径的相互作用以调节宿主生物学，以及从寄生虫的进化中学习如何操纵免疫系统。在未来五多年来，我的实验室将确定脂质介导的免疫信号传导的关键遗传途径，并确定分子宿主，寄生虫的相互作用我们的具体重点将是：1）建立实验管道，寄生虫衍生的蛋白质和调节宿主生物学的小分子，2）决定寄生虫的作用，我们识别的分子，从脂肪酸和视黄醇结合（FAR）蛋白家族的成员开始，3）阐明寄生虫分子和宿主途径之间的分子相互作用，以及4）表征类花生酸信号在果蝇，免疫遗传模型。我实验室研究的一个主要策略是联合收割机将计算机模拟、体外和体内实验方法与已建立的感染模型相结合，我们对果蝇生物学及其强大遗传学的深刻理解，不仅揭示了果蝇的结合靶点，寄生虫的蛋白质和分子在活动性感染，而且还确定其对感染结果的影响。我们总体目标是了解线虫寄生虫如何改变宿主生物学，以便成功地感染它们。这包括寄生虫逃避和/或抑制宿主免疫的能力，这对人类健康很重要，至少有两种方式。首先，线虫感染仍然是全球发病率和死亡率的主要来源，影响了全球25%以上的人口增加耐药性和反复感染的化合物这个问题第二，越来越多的证据表明线虫感染的免疫调节作用可以抑制甚至消除自身免疫性疾病的病理，如克罗恩病，炎症性肠病和乳糜泻。了解线虫如何抑制免疫系统将导致针对线虫感染的新的治疗和疫苗接种策略，并可能揭示新的途径用于治疗自身免疫性疾病我们将采用一个强大的模型系统来探测免疫调节，线虫，以确定特定的分泌蛋白和小分子，以及信号通路，他们以有效地操纵宿主免疫。