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: 10652503
• 负责人: Robert A Dorschner
• 金额: $ 15.41万
• 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/10652503
• 关键词: Address; Adhesions; Alternative Therapies; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Automobile Driving; Biological Assay; Biology; Biometry; Bone Marrow Examination; 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; Research Training; 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; career; career development; clinical training; 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.

项目总结/摘要： 此K 08应用程序旨在为医学博士Robert Dorschner提供科学培训和专业 发展需要成为一个独立的调查员在皮肤宿主防御领域。的 耐甲氧西林金黄色葡萄球菌（MRSA）的出现显著增加了皮肤 软组织感染（SSTI）。非常需要创新，以更好地了解 皮肤和开发替代疗法。中性粒细胞是皮肤宿主防御的关键组成部分， 缺乏针对嗜中性粒细胞的治疗。本提案的长期目标是通过一个项目培训PI 这将促进对调节中性粒细胞募集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 ECRG 4促进早期中性粒细胞募集到皮肤损伤并调节CD 44表达。中央 假设ECRG 4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CD 44信号传导的能力。该项目的基本原理是 新的中性粒细胞募集机制的确定将使分子的治疗靶向 如ECRG 4用于嗜中性粒细胞导向疗法，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ECRG 4 KO小鼠和人白细胞，以：1） 确定ECRG 4在宿主防御皮肤金黄色葡萄球菌感染中的作用，2）评估其在宿主防御皮肤金黄色葡萄球菌感染中的作用。 用体内和离体模型调节中性粒细胞，和3）确定ECRG 4调节的CD 44的作用 表达对中性粒细胞募集和功能的影响。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， 治疗为了实现这一目标，Dorschner博士组建了一个跨部门的指导团队， 让初级研究人员开始独立的研究生涯。他的主要导师来自 布莱恩Eliceiri博士，博士，在免疫细胞贩运和炎症的专家，和安德鲁博士 贝尔德博士，伤口愈合专家。来自卫生部的其他临床医生-科学家导师 皮肤科在皮肤免疫和炎症研究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， 使用小鼠和人类模型的中性粒细胞生物学和信号传导2）资助写作、临床研究的培训 3）为成功的R 01提交生成数据，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 科学环境在UCSD的外科和皮肤科部门。本培训计划建立在 博士Dorschner以前的研究和临床培训使他成为一名领先的临床科学家， R 01资助的独立研究项目集中于中性粒细胞驱动的皮肤炎症反应。