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

• 批准号: 10207472
• 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
• 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/10207472
• 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; Infectious Skin Diseases; Inflammation; Inflammatory Response; 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; Skin injury; 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

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 发展需要成为皮肤宿主防御领域的独立调查者。这个 耐甲氧西林金黄色葡萄球菌(MRSA)的出现显著增加了皮肤的发病率 和软组织感染(SSTI)。我们非常需要创新，以更好地理解东道主对 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 目前缺乏针对中性粒细胞的治疗方法。这项提议的长期目标是通过一个项目来培训PI 这将促进对调节中性粒细胞招募和激活的固有机制的理解。 皮肤发炎和感染。他的初步数据表明，白细胞表面蛋白 ECRG4促进中性粒细胞早期募集到皮肤损伤，并调节CD44的表达。中环 假设ECRG4增强炎症反应以抑制和消除皮肤感染 通过其放大中性粒细胞募集和调节CD44信号的能力。这个项目的基本原理是 确定新的中性粒细胞募集机制将使分子靶向治疗成为可能 例如ECRG4用于中性粒细胞指导的治疗，以增强宿主对抗生素耐药微生物的防御。Dr。 多施纳将把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在宿主抵抗皮肤金黄色葡萄球菌感染中的作用，2)评估其 体内和体外模型对中性粒细胞的调节，以及3)ECRG4调节CD44的作用 中性粒细胞募集和功能的表达。这些发现将展示一种新的机制 控制感染的早期炎症反应可转化为抗感染药物的发展 治疗。为了实现这一目标，多施纳博士组建了一个有经验的跨部门指导团队 启动初级调查人员进入独立研究职业生涯。他的主要导师来自教育部 外科医生是免疫细胞贩运和炎症方面的专家Brian Eliceiri博士和Andrew博士 贝尔德博士，伤口愈合方面的专家。额外的临床医生-科学家导师来自 皮肤科在皮肤免疫和炎症研究以及临床科学家方面提供进一步的专业知识 职业发展。该培训计划实施1)获取科学和技术专门知识 利用小鼠和人类模型进行中性粒细胞生物学和信号传递2)赠款撰写、临床研究方面的培训 和生物统计3)为成功的R01提交生成数据，以及4)计划过渡到 通过持续的职业发展实现独立。这项工作发生在杰出的 加州大学圣迭戈分校外科和皮肤科的科学环境。这项培训计划的基础是 多施纳医生之前的研究和临床培训，使他成为一名领先的临床医生兼科学家，患有 R01资助的独立研究项目侧重于中性粒细胞驱动的皮肤炎症反应。