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.
This project aims to elucidate a novel pathway in early neutrophil recruitment that appears critical to host defense against skin and soft tissue infections. It addresses the decreasing ability of our antibiotic armamentarium to treat increasingly resistant microbes, a global health crisis that is driving a need to develop anti-infective therapies that augment the host immune response. This work is relevant to public health as it will provide new targets for the development of alternative antimicrobial therapies utilizing innate host defense mechanisms, which are currently lacking.
