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Ad5 Fiber Entry and Trafficking in Lacrimal Acini

Ad5 纤维在泪腺泡中的进入和运输

基本信息

批准号：
7394357
负责人：
Sarah F Hamm-Alvarez
金额：
$ 34.9万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-03 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7394357
关键词：
Acinar Cell Acinus organ component Adenoviruses Affect American Antisense Oligonucleotides Autoimmune Diseases Autoimmune Process Binding Capsid Capsid Proteins Cells Coxsackie Viruses Cytosol DNA Data Dependence Development Diagnosis Disease Disease Progression Distant Drug Delivery Systems Endocytosis Etiology Eye diseases Fiber Functional disorder Future Goals Heparin Heparitin Sulfate Histocompatibility Antigens Class I Intracellular Membranes Knowledge Lacrimal gland structure Lead Liquid substance Mediating Membrane Molecular Morbidity - disease rate Oligonucleotides Oryctolagus cuniculus Participant Pathway interactions Peptide antibodies Peptides Pharmaceutical Preparations Proteins Recombinants Relative (related person)Research Serotyping Site Sjogren&apos s Syndrome Small Interfering RNA Surface Symptoms System Testing Therapeutic Viral Virus Woman Work adenovirus penton protein adenovirus receptor base eye dryness glycosaminoglycan receptor insight lacrimal lacrimal acini next generation novel ocular surface polysulfated glycosaminoglycan prospective receptor receptor binding receptor function remediation research study therapeutic target trafficking uptake

项目摘要

A major contribution to ocular morbidity is lacrimal dysfunction, affecting over 10 million Americans. The principal cell of the lacrimal gland and primary contributor of proteins into ocular surface fluid is the lacrimal acinar cell, which is the target of much of the ocular research into the etiology of dry eye diseases including the severe autoimmune disease, Sjogren's syndrome. Ongoing studies are now shedding insights into the precise mechanisms involved in initiation, development and progression of disease, suggesting that dentification of prospective therapeutic targets is likely in the not so distant future. However, we are still very limited in our ability to specifically target the next generation of macromolecular drugs, particularly DNA-, protein- or peptide based drugs, to the lacrimal gland, raising the possibility that we may soon identify advanced therapies for treatment of severe dry eye diseases but will be unable to deliver these drugs to the target site. Our focus here is to explore the unusual and possibly unique uptake mechanism utilized for lacrimal acinar internalization of adenovirus serotype 5 (Ad5). We have demonstrated in lacrimal acinar cells that Ad5 utilizes a unique fiber-dependent internalization pathway, in contrast to the penton-dependent internalization described in other systems. We hypothesize that Ad5 may use multiple fiber receptors for binding and entry in lacrimal acini, and further that one or more of these entry pathways is either unusually robust or unique to lacrimal acini, explaining the unusual fiber-dependence of entry in tandem with the high efficiency of viral transduction in lacrimal acini. We propose to characterize the participants in this novel fiber-dependent internalization pathway at the molecular level, with a particular focus on coxsackievirus adenovirus receptor, major histocompatibility complex class 1 and heparin sulfate-glycosaminoglycan receptors, and their different modes of endocytosis. The aims are as follows: Aim #1. Does coxsackievirus adenovirus receptor mediate fiber-dependent Ad5 internalization or free fiber internalization in lacrimal acini? Aim #2. What other receptors participate in fiber-dependent Ad5 internalization or free fiber internalization in lacrimal acini? Aim #3. What intracellular trafficking pathways mediate fiber-dependent Ad5 internalization or free fiber internalization in lacrimal acini? At the conclusion of this work, we will have elucidated the contributions of specific receptors and endocytic internalization pathways responsible for fiber-dependent internalization of Ad5. We will have determined to what extent the recombinant fiber or knob, the terminal region of the fiber protein, can recapitulate these pathways. Finally, we will have tested proof-of-principle experiments to determine whether fiber or knob can facilitate entry of antisense oligonucleotides and proteins into lacrimal acinar cytosol.

造成眼部疾病的主要原因是泪道功能障碍，影响了超过1000万美国人。的