Molecular Pharmacology of NKT Cell Agonists

NKT 细胞激动剂的分子药理学

基本信息

批准号：
8850805
负责人：
Luc Teyton
金额：
$ 71.78万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850805
关键词：
Activated Lymphocyte Address Adjuvant Agonist Animals Antigens Attention B-Lymphocytes Behavior Binding Biochemistry Biological Models Biology Biotechnology CD8B1 gene Cancer Vaccines Catabolism Cell Communication Cell physiology Cells Cellular biology Chemicals Chemistry Cholesterol Cholesterol Homeostasis Chronic Clinical Clinical Research Clinical Trials Communicable Diseases Dendritic Cells Development Disease Equipment Family Funding Galactosylceramides Genetic Polymorphism Glycolipids Goals Grant Health Human Human Resources Immune Immune response Immunity Immunization Immunologist Immunomodulators Immunotherapy In Vitro Infection Intervention Knowledge Laboratories Learning Link Lipid Biochemistry Lipids Lipoprotein Receptor Lipoproteins Low Density Lipoprotein Receptor Lymphocyte Mass Spectrum Analysis Medicine Metabolism Molecular Mus Natural Immunity Pharmaceutical Preparations Pharmacologic Substance Pharmacology Process Property Protein Engineering Proteins Proteomics Recombinant Proteins Recruitment Activity Serum System Techniques Therapeutic Time Training Translating Translations United States National Institutes of Health Vaccination Work base cancer immunotherapy cytokine design disorder prevention drug candidate fatty acid amide hydrolase in vivo in vivo Model interest killer T cell metabolomics novel particle protein expression research clinical testing response scavenger receptor sensor success tool translational study uptake usability vaccine development

项目摘要

DESCRIPTION (provided by applicant): NKT cells offer an enormous therapeutic potential if we learn how to manipulate them in vivo. As cellular adjuvants of immunity, NKT cells prime and control the maturation of dendritic cells in al infectious contexts. As such, the recruitment of these cells could be critical to vaccine development, immunotherapy of chronic infectious diseases, prevention of infection, and cancer vaccines. However, success will rely heavily on our ability to translate the knowledge of mouse NKT biology to humans. For instance, the pharmacology of compounds capable of activating NKT cells is almost unexplored as are cellular uptake and catabolism. Since, activators of NKT cells are glycolipids, it is most likely that lipoprotein and scavenger receptor polymorphism in human will heavily influence the potency of this new family of immunomodulators. We propose to address some fundamental aspects of the molecular pharmacology of NKT agonists in mice and humans to help a successful use of those molecules in medicine. This goal will be attained through 3 specific aims: Aim 1: Proteomic studies of NKT cell agonist transport and metabolism. Based on our previous work, we hypothesize that NKT agonists have a unique biology when compared to other lipids. Original tools need to be designed and used in the context of NKT biology to drive substantial progress in the field and its translation to clinical studies. We will combine novel chemistry and recombinant protein engineering to access the molecular pharmacology of NKT agonists. Aim 2: Transport of NKT cell agonists. Using traditional serum biochemistry, we have isolated and characterized the function of the association between FAAH and ¿GalCer. Using proteomic approaches we have now profiled serum for all ¿GalCer-associated proteins. We hypothesize that many of these proteins will impact positively or negatively the biology of NKT agonists. The study of each of these proteins will be carried out using a robust experimental system combining recombinant protein expression, in vitro biophysical and functional studies, and in vivo model systems of vaccination before being translated to human cells. Aim 3: Cellular uptake and catabolism of NKT cell agonists. Uptake, processing and catabolism of NKT agonists have been only superficially examined. We will combine proteomics studies with novel biochemistry and cell biology approaches to understand the delivery and processing of NKT antigens to CD1d loading compartments. As NKT agonists are entering rapidly the clinical field, the knowledge that we will acquire through the current proposal will be critical for successful translational studies.

描述（由申请人提供）：如果我们学会如何在体内操纵它们，NKT 细胞将具有巨大的治疗潜力，NKT 细胞可以在所有感染环境中启动并控制树突状细胞的成熟。然而，成功将在很大程度上依赖于我们将小鼠 NKT 生物学知识转化为人类的能力，例如能够激活的化合物的药理学。 NKT 细胞的细胞摄取和分解代谢几乎尚未被探索，因为 NKT 细胞的激活剂是糖脂，因此人类的脂蛋白和清道夫受体多态性很可能会严重影响这一新免疫调节剂家族的效力。 NKT 激动剂在小鼠和人类中的分子药理学的基本方面，以帮助这些分子在医学中的成功应用。这一目标将通过 3 个具体目标来实现：目标 1：NKT 细胞激动剂转运和代谢的蛋白质组学研究根据我们之前的工作，我们发现与其他脂质相比，NKT 激动剂具有独特的生物学特性，需要在 NKT 生物学背景下设计和使用原始工具来驱动。我们将在该领域取得实质性进展并将其转化为临床研究。结合新颖的化学和重组蛋白质工程来了解 NKT 激动剂的分子药理学目标 2：NKT 细胞激动剂的转运，我们分离并表征了 FAAH 和 ¿使用蛋白质组学方法，我们现在已经对所有人的血清进行了分析 ¿ GalCer 相关蛋白。我们追求这些蛋白中的许多会对 NKT 激动剂的生物学产生积极或消极的影响。对每种蛋白的研究将使用结合重组蛋白表达、体外生物物理和功能研究的强大实验系统进行。目标 3：NKT 细胞激动剂的细胞摄取和分解代谢 NKT 激动剂的摄取、加工和分解代谢。我们将把蛋白质组学研究与新的生物化学和细胞生物学方法结合起来，以了解 NKT 抗原向 CD1d 装载室的传递和加工，随着 NKT 激动剂迅速进入临床领域，我们将通过当前提案获得的知识。对于成功的转化研究至关重要。