The role of the ECRG4 in Host Defense of Staph Aureus Infection

ECRG4 在金黄色葡萄球菌感染宿主防御中的作用

基本信息

批准号：
10040337
负责人：
Robert A Dorschner
金额：
$ 15.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10040337
关键词：
Address Adhesions Alternative Therapies Anti-Infective Agents Antibiotic Resistance Antibiotics Automobile Driving Biological Assay Biology Biometry Bone Marrow CD44 gene Cells Cellular biology Clinical Clinical Research Communities Cutaneous Data Dermatology Development Diabetes Mellitus Disease Doctor of Philosophy Elements Environment Face Failure Functional disorder Funding Generations Goals Grant Hospitals Host Defense Host Defense Mechanism Human Hyaluronic Acid Immune Immune response Immunity Immunophenotyping Immunotherapy Impairment Individual Infection Inflammation Inflammatory Response Injury Knockout Mice Knowledge Lesion Leukocytes Mediating Membrane Proteins Mentors Microbe Microbial Antibiotic Resistance Modeling Molecular Biology Morbidity - disease rate Mus Neutropenia Neutrophil Activation Neutrophil Infiltration Operative Surgical Procedures Pathway interactions Positioning Attribute Prevalence Production Public Health Regulation Research Research Personnel Resistance Respiratory Burst Risk Role Scientist Sepsis Signal Transduction Skin Skin Tissue Soft Tissue Infections Soft Tissue Injuries Staphylococcus aureus infection Surgical Wound Infection Systemic disease Technical Expertise Techniques Testing Traction Training Translating Work Writing antimicrobial antimicrobial peptide base career career development cytokine design diabetic diabetic patient experience fighting global health human model in vivo innovation methicillin resistant Staphylococcus aureus migration mortality mouse model neutrophil novel pathogen programs recruit response targeted treatment therapeutic target therapy development trafficking wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT: This K08 application is designed to provide Dr. Robert Dorschner, MD, the scientific training and professional development required to become an independent investigator in the field of cutaneous host defense. The advent of methicillin resistant staphylococcus aureus (MRSA) has significantly increased the morbidity of skin and soft tissue infections (SSTIs). There is a great need for innovation to better understand host defense of the skin and to develop alternative therapies. Neutrophils are a key component of cutaneous host-defense, yet neutrophil-targeted therapies are lacking. The long-term goal of this proposal is to train the PI through a project that will advance an understanding of innate mechanisms that regulate neutrophil recruitment and activation in cutaneous inflammation and infection. His preliminary data demonstrate that the leukocyte surface protein ECRG4 promotes early neutrophil recruitment to cutaneous injury and regulates CD44 expression. The central hypothesis is that ECRG4 enhances the inflammatory response to contain and eliminate cutaneous infection through its ability to amplify neutrophil recruitment and regulate CD44 signaling. The rationale for this project is that a determination of novel neutrophil recruitment mechanisms will enable therapeutic targeting of molecules like ECRG4 for neutrophil-directed therapies to enhance host defense against antibiotic resistant microbes. Dr. Dorschner will apply molecular and cell biology techniques to ECRG4 KO mice and human leukocytes to: 1) Determine the role of ECRG4 in host defense against cutaneous staph aureus infection, 2) Assess its regulation of neutrophils with in vivo and ex vivo models, and 3) Define the effect of ECRG4 regulated CD44 expression on neutrophil recruitment and function. These findings will demonstrate a novel mechanism controlling early inflammatory responses to infection that can be translated to the development of anti-infective therapies. To achieve this, Dr. Dorschner has assembled an interdepartmental mentoring team with experience launching junior investigators into independent research careers. His primary mentors from the Department of Surgery are Dr. Brian Eliceiri, PhD, an expert in immune cell trafficking and inflammation, and Dr. Andrew Baird, PhD, an expert in wound healing. Additional clinician-scientist mentors from the Department of Dermatology provide further expertise in cutaneous immunity and inflammation research and clinician-scientist career development. This training plan implements 1) acquisition of scientific and technical expertise in neutrophil biology and signaling using mouse and human models 2) training in grant writing, clinical research and biostatistics 3) generation of data for a successful R01 submission, and a 4) planned transition to independence through ongoing professional development. This work takes place within the outstanding scientific environment at UCSD in the Departments of Surgery and Dermatology. This training plan builds on Dr. Dorschner's previous research and clinical training to position him as a leading clinician-scientist with an independent R01-funded research program focused on neutrophil driven cutaneous inflammatory responses.

项目摘要/摘要：此 K08 应用程序旨在为医学博士 Robert Dorschner 提供科学培训和专业知识成为皮肤宿主防御领域的独立研究者所需的发展。这耐甲氧西林金黄色葡萄球菌（MRSA）的出现显着增加了皮肤病的发病率和软组织感染（SSTI）。非常需要创新来更好地了解宿主的防御皮肤并开发替代疗法。中性粒细胞是皮肤宿主防御的关键组成部分，但缺乏针对中性粒细胞的治疗方法。该提案的长期目标是通过项目培训 PI 这将促进对调节中性粒细胞招募和激活的先天机制的理解皮肤炎症和感染。他的初步数据表明，白细胞表面蛋白 ECRG4 促进早期中性粒细胞募集至皮肤损伤并调节 CD44 表达。中央假设 ECRG4 增强炎症反应以遏制和消除皮肤感染通过其放大中性粒细胞募集和调节 CD44 信号传导的能力。该项目的理由是确定新的中性粒细胞招募机制将使分子的治疗靶向成为可能例如 ECRG4 用于中性粒细胞定向治疗，以增强宿主对抗生素耐药微生物的防御。博士。 Dorschner 将分子和细胞生物学技术应用于 ECRG4 KO 小鼠和人类白细胞：1) 确定 ECRG4 在宿主防御皮肤金黄色葡萄球菌感染中的作用，2) 评估其体内和离体模型对中性粒细胞的调节，以及 3) 定义 ECRG4 调节 CD44 的作用中性粒细胞募集和功能的表达。这些发现将证明一种新的机制控制对感染的早期炎症反应，这可以转化为抗感染药物的开发疗法。为了实现这一目标，Dorschner 博士组建了一支经验丰富的跨部门指导团队让初级研究人员进入独立研究生涯。他的主要导师来自负责手术的是免疫细胞运输和炎症方面的专家 Brian Eliceiri 博士和 Andrew 博士贝尔德博士，伤口愈合专家。来自该部门的其他临床医生科学家导师皮肤科提供皮肤免疫和炎症研究以及临床科学家的进一步专业知识职业发展。该培训计划实施 1) 获得以下方面的科学和技术专业知识使用小鼠和人体模型进行中性粒细胞生物学和信号传导 2) 拨款写作、临床研究方面的培训 3) 为成功提交 R01 生成数据，以及 4) 计划过渡到通过持续的专业发展实现独立。这项工作发生在杰出的加州大学圣地亚哥分校外科和皮肤科的科学环境。该培训计划建立在 Dorschner 博士之前的研究和临床培训使他成为一位领先的临床医生科学家 R01 资助的独立研究项目专注于中性粒细胞驱动的皮肤炎症反应。