Unsaturated glycoceramide as novel platform for mucosal vaccine and drug delivery

不饱和甘油酰胺作为粘膜疫苗和药物输送的新平台

基本信息

批准号：
8145606
负责人：
WAYNE I LENCER
金额：
$ 21.51万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8145606
关键词：
Address Adjuvant Agonist Antigens Apical Area Asthma Biological Assay Biology Blood Glucose Cell surface Cells Ceramides Cholera Toxin Dendritic Cells Destinations Development Drug Delivery Systems Endocytosis Endosomes Environment Epithelial Epithelial Cells Fatty Acids Flagellin Ganglioside GM1 Gene Expression Goals Hormones Immune In Vitro Inflammatory Bowel Diseases Injection of therapeutic agent Intestines Invaded Lamina Propria Leptin Life Ligands Link Lipids Lysosomes Measurable Measures Membrane Protein Traffic Memory B-Lymphocyte Methods Modeling Mucosal Immune Responses NF-kappa B Nose Oral Ovalbumin Pathway interactions Peptides Play Proteins Recycling Research Role Salmonella Saturated Fatty Acids Sorting - Cell Movement Structure Surface T-Lymphocyte TLR5 gene Technology Testing Therapeutic Tight Junctions Tissues Toll-like receptors Toxic effect Translating Vaccine Adjuvant Vaccine Antigen Variant Work absorption apical membrane base clinical application diabetic glucagon-like peptide glucose tolerance glycolipid receptor improved in vitro testing in vivo innovation late endosome lipid structure lipid transport molecular carrier monolayer mucosal vaccination mucosal vaccine novel pathogen peptide hormone prevent programs public health relevance response therapeutic protein therapeutic vaccine trafficking vaccine delivery

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to test if our recent discovery on lipid trafficking in epithelial cells can be translated to clinical applications. Specifically, we will test the utility of using "short or unsaturated" ceramide-based lipids as molecular carriers to deliver therapeutic peptides or vaccine adjuvants across mucosal epithelial barriers. Mucosal surfaces represent vast areas where host tissues are separated from the environment only by a delicate but highly effective single layer of columnar epithelial cells, joined by tight junctions that are impermeable to proteins and even small peptides. So far, the lack of rational and efficient methods to circumvent this barrier has prevented the application of most therapeutic proteins for oral or nasal drug delivery and for mucosal vaccines. In the course of our studies on the biology of the glycolipid receptor for cholera toxin, ganglioside GM1, we recently discovered that the structure of the ceramide (lipid) domain dictates GM1 trafficking in epithelial cells. When applied apically, GM1-ceramides containing "short" C12:0 or "kinked chain" unsaturated C16:1 fatty acids (GM1short/unsat) enter the common/recycling endosome. Here, they are sorted for transport to various intracellular destinations and into the "transcytotic" pathway to the basolateral cell surface. In contrast, the GM1-ceramides with fully saturated fatty acid chains (C16:0 or longer) (GM1 long/sat) are instead transported to the late endosome and lysosome for degradation. In this exploratory project, we will test whether this basic discovery can be harnessed for transepithelial delivery of a bioactive peptide or protein adjuvant, both of which have clinical applications. We will link GM1 molecules containing unsaturated "kinked" or saturated fatty acids to the therapeutic peptide hormone glucagon-like peptide-1 (GLP1), which acts to regulate blood sugar (Aim 1); and to the TLR5-agonist FliC (Salmonella flagellin), which we use here to model a mucosal vaccine adjuvant (Aim 2). These studies will test a novel platform for transport of therapeutic/vaccine molecules across mucosal surfaces. There is great need for non-parental delivery of therapeutic peptides and proteins. Improved mucosal vaccine strategies are greatly needed for protection against pathogens, the vast majority of which invade via mucosal surfaces. PUBLIC HEALTH RELEVANCE: The goal of this application is to develop a way to allow for oral or nasal administration of therapeutic proteins and vaccines. Normally such proteins are not absorbed and must be delivered by injection; severely limiting therapeutic applications.

描述（由申请人提供）：该提案的目的是测试我们最近在上皮细胞中脂质运输的发现是否可以转化为临床应用。具体而言，我们将测试使用“短或不饱和神经酰胺的脂质作为分子载体，以在粘膜上皮屏障中输送治疗性肽或疫苗佐剂。粘膜表面代表了广阔的区域，在这些区域中，只有通过细腻但有效的柱状上皮细胞的单层单层将宿主组织与环境分离，并由蛋白质甚至小肽不可渗透的紧密连接连接。到目前为止，缺乏规避这种障碍的理性和有效方法阻止了大多数治疗蛋白用于口服或鼻药物以及粘膜疫苗的应用。在关于霍乱毒素糖脂受体生物学的研究过程中，神经节GM1，我们最近发现，神经酰胺（脂质）结构域的结构决定上皮细胞中的GM1运输。当顶端应用时，含有“短” C12：0或“扭结链”不饱和C16：1脂肪酸（GM1-Short/UNSAT）的GM1-钙酰胺输入常见/回收的内体。在这里，它们被分类用于运输到各种细胞内目的地，并进入到基底外侧细胞表面的“跨介质”途径。相比之下，具有完全饱和的脂肪酸链（C16：0或更长时间）（GM1长/SAT）的GM1-钙酰胺被转运到晚期内体和溶酶体以降解。在这个探索性项目中，我们将测试是否可以利用这种基本发现来递送生物活性肽或蛋白质辅助剂，这两者都有临床应用。我们将将含有不饱和“扭结”或饱和脂肪酸的GM1分子与治疗性肽激素胰高血糖素样肽-1（GLP1）联系起来，该肽可用于调节血糖（AIM 1）；以及TLR5激动剂（Salmanella鞭毛蛋白），我们在这里用来对粘膜疫苗佐剂进行建模（AIM 2）。这些研究将测试一个新型的平台，用于跨粘膜表面的治疗/疫苗分子运输。非常需要非父母递送治疗性肽和蛋白质。为了防止病原体，非常需要改善粘膜疫苗策略，其中绝大多数通过粘膜表面侵入。公共卫生相关性：本应用的目的是开发一种允许口服或鼻腔治疗蛋白和疫苗的方法。通常，这种蛋白质不被吸收，必须通过注射递送；严重限制治疗应用。