Regulation of vitamin A metabolism during Schistosoma mansoni infection

曼氏血吸虫感染期间维生素A代谢的调节

基本信息

批准号：
8415947
负责人：
Png Loke
金额：
$ 39.72万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8415947
关键词：
Affect Antigen-Presenting Cells Cell Differentiation process Cell physiology Cells Cessation of life Chronic Coculture Techniques Dendritic Cells Dichloromethylene Diphosphonate Disease Enzymes Equilibrium Feedback Genes Genetic Goals Health Helminths Human ITGAX gene Immune Immune response In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Inflammatory disease of the intestine Interleukin-4 Internal Ribosome Entry Site Intervention Intestines Knock-in Mouse Knowledge Kupffer Cells Lamina Propria Lead Liposomes Liver Mediating Metabolism Micronutrients Molecular Morbidity - disease rate Mouse Strains Mucosal Immunity Mus Nutritional status Pathogenesis Pathology Pathway interactions Play Process Production Regulation Regulatory T-Lymphocyte Reporter Retinoic Acid Receptor Role Schistosoma mansoni Schistosoma mansonii infection Schistosomiasis Splenocyte Symbiosis System T-Lymphocyte Testing Th2 Cells Transgenic Organisms Tretinoin Vitamin A Vitamin A Deficiency cell type cytokine design egg in vivo liver inflammation loss of function macrophage mortality novel therapeutic intervention public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Helminths such as Schistosoma mansoni are remarkably efficient at establishing chronic infections with limited inflammatory pathology in some of their hosts, while in other infected people they can cause severe morbidity and they are a major health problem worldwide. Our long-term goal is to understand how liver and intestinal inflammation is regulated during S. mansoni infection. Perhaps the balance between pathogenesis and symbiosis is dependent on the nutritional status of infected individuals. However, we have a very limited understanding of the molecular mechanisms that underpin the relationship between helminth infections, nutritional status and inflammatory responses. Micronutrients such as vitamin A may play a critical role in regulating the inflammatory immune response during helminth infection. Recently, vitamin A metabolism and retinoic acid (RA) has emerged to be important in regulating mucosal immunity. Aldh1a2 is the major enzyme regulating RA production by antigen presenting cells in the gut. Alternatively activated macrophages (AAM) induced by IL-4 have been shown to play an important role in regulating liver and intestinal inflammation during S. mansoni infection, although the mechanism of regulation is not known. Here, we hypothesize that RA production via Aldh1a2 activity in AAM plays an important role in promoting Th2 responses and hence regulating liver and intestinal inflammation during S. mansoni infection. We have preliminary results showing that Aldh1a2 is upregulated by AAM in vitro and in vivo during helminth infection. By infecting vitamin A deficient mice with S. mansoni, we have found that Th2 responses are strikingly reduced, whereas surprisingly, we see an increase in regulatory T cells. We have previously shown that AAMs could bias T helper cell differentiation pathways from Th1 to Th2 cells and RA might therefore provide a mechanism. Since the Aldh1a2 deficient mice are embryonically lethal, we have also designed and generated a transgenic reporter mouse with an inducible deletion system. We are also generating mice with cell type specific (macrophage and dendritic cell) deletions of the Aldh1a2 gene. In this proposal, our specific aims are: (1) to determine if RA production by AAM plays a role in enhancing Th2 responses during in vivo S. mansoni infection; (2) to determine if AAM can influence T helper cell differentiation and function through RA in vitro; (3) to characterize new mouse strains that will provide genetic loss of function evidence for cell specific roles of Aldh1a2 in promoting Th2 responses during S. mansoni infection. The results of these studies will provide us with a framework to devise new ways of regulating inflammation through manipulating the capacity of macrophages to control vitamin A metabolism.

描述（由申请人提供）：诸如曼氏血吸虫之类的蠕虫在某些宿主中非常有效地建立慢性感染，且炎症病理学有限，而在其他感染者中，它们可能导致严重的发病率，并且它们是世界范围内的主要健康问题。我们的长期目标是了解曼氏沙门氏菌感染期间肝脏和肠道炎症是如何调节的。也许发病机制和共生之间的平衡取决于感染个体的营养状况。然而，我们对蠕虫感染、营养状况和炎症反应之间关系的分子机制了解非常有限。维生素 A 等微量营养素可能在调节蠕虫感染期间的炎症免疫反应中发挥关键作用。最近，维生素 A 代谢和视黄酸 (RA) 在调节粘膜免疫方面发挥着重要作用。 Aldh1a2 是调节肠道中抗原呈递细胞产生 RA 的主要酶。 IL-4诱导的选择性活化巨噬细胞（AAM）已被证明在曼氏沙门氏菌感染期间调节肝脏和肠道炎症中发挥重要作用，但调节机制尚不清楚。在这里，我们假设 AAM 中 Aldh1a2 活性产生的 RA 在促进 Th2 反应，从而调节曼氏沙门氏菌感染期间的肝脏和肠道炎症方面发挥着重要作用。我们的初步结果表明，在蠕虫感染期间，AAM 在体外和体内均上调 Aldh1a2。通过用曼氏沙门氏菌感染缺乏维生素 A 的小鼠，我们发现 Th2 反应显着降低，而令人惊讶的是，我们发现调节性 T 细胞有所增加。我们之前已经表明，AAM 可以使 T 辅助细胞分化途径从 Th1 细胞偏向 Th2 细胞，因此 RA 可能提供一种机制。由于 Aldh1a2 缺陷小鼠具有胚胎致死性，我们还设计并生成了具有诱导缺失系统的转基因报告小鼠。我们还培育出具有特定细胞类型（巨噬细胞和树突状细胞）Aldh1a2 基因缺失的小鼠。在本提案中，我们的具体目标是：（1）确定AAM产生的RA是否在体内曼氏沙门氏菌感染过程中增强Th2反应中发挥作用； (2) 确定AAM是否可以在体外通过RA影响T辅助细胞的分化和功能； (3) 表征新的小鼠品系，这些小鼠品系将为 Aldh1a2 在曼氏沙门氏菌感染期间促进 Th2 反应的细胞特异性作用提供遗传功能丧失的证据。这些研究的结果将为我们提供一个框架，通过操纵巨噬细胞控制维生素 A 代谢的能力来设计调节炎症的新方法。