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：
9065492
负责人：
Luc Teyton
金额：
$ 72.73万
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9065492
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 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 novel therapeutics 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）：如果我们学习如何在体内操纵它们，则NKT细胞具有巨大的治疗潜力。作为免疫学的细胞调节体，NKT细胞在感染性环境中启发并控制树突状细胞的成熟。因此，这些细胞的募集对于疫苗发育，慢性感染的免疫疗法，预防感染和癌症疫苗可能至关重要。但是，成功将严重依赖我们将小鼠NKT生物学知识转化为人类的能力。例如，能够激活NKT细胞的化合物的药理学几乎是出乎意料的，细胞摄取和分解代谢也是出乎意料的。由于NKT细胞的激活剂是糖脂，因此人类中最有可能脂蛋白和清道夫受体多态性会严重影响这一新的免疫调节剂家族的效力。我们建议解决小鼠和人类NKT激动剂分子药理学的某些基本方面，以帮助成功地使用这些分子。该目标将通过3个特定目的实现：目标1：NKT细胞激动剂运输和代谢的蛋白质组学研究。根据我们以前的工作，我们假设与其他脂质相比，NKT激动剂具有独特的生物学。原始工具需要在NKT生物学的背景下设计和使用，以推动该领域的实质进展及其转化为临床研究。我们将结合新的化学和重组蛋白工程，以获取NKT激动剂的分子药理学。目标2：NKT细胞激动剂的运输。使用传统的血清生物化学，我们已经孤立并表征了法族和``Galcer之间的关联功能''的功能。使用蛋白质组学方法，我们现在已经为所有与Galcer相关的蛋白质介绍了血清。我们假设许多这些蛋白质将对NKT激动剂的生物学产生积极或负面影响。这些蛋白质中的每一种都将使用结合重组蛋白表达，体外生物物理和功能研究的稳健实验系统以及在转化为人类细胞之前的体内疫苗系统。目标3：NKT细胞激动剂的细胞摄取和分解代谢。仅对NKT激动剂的吸收，加工和分解代谢。我们将将蛋白质组学研究与新颖的生物化学和细胞生物学方法相结合，以了解NKT抗原向CD1D载荷室的递送和加工。随着NKT激动剂正在迅速进入临床领域，我们将通过当前建议获得的知识对于成功的翻译研究至关重要。