Utilizing a Novel Skin-on-a-Chip Model to Investigate Extramedullary Granulopoiesis and Immune Responses in Human Skin - PROJECT SUMMARY The ultimate goal of this F31 Ruth L. Kirchstein NRSA is to request support to address a fundamental gap in knowledge of the local immune response in bacterial skin infections. There is an escalating threat of antibiotic skin infections worldwide. Persons who suffer from neutropenia, such as diabetic patients or persons undergoing chemotherapy treatment, are particularly at risk for developing a severe antibiotic-resistant skin infection. Their first line of innate immune defense, neutrophils, are quantitively insufficient in both circulation and at the site of infection, leading to complications. Meanwhile, otherwise healthy individuals are increasingly suffering from these life-threatening infections. Traditionally it has been thought that neutrophils traffic to a site of infection/wounding solely through circulation, however, new studies are showing this is no longer the case, at least in mice. We now understand that the precursors to these neutrophils, hematopoietic stem and progenitor cells (HSPCs), also traffic to the sites of these infections, and are able to locally produce functional neutrophils capable of combating infection. While unable to directly test in humans, our innovative skin-on-a-chip model offers a unique platform to monitor these interactions in a controlled, sterile environment. This will provide us mechanistic insight into HSPC migration into human skin and granulopoiesis in response to bacterial and inflammatory stimuli. Building on results in my preliminary data, I will carry out this project in two steps: 1. Demonstrate the HSPC signaling axis of SDF-1/CXCR4 between soluble and membrane-bound SDF-1 is necessary to attract and maintain a stable population of HSPCs in the skin. 2. Demonstrate that direct TLR2 activation on HSPCs enhances DAMP-mediated local granulopoiesis within the infected skin environment. This research promises to offer novel insights into the immune responses in the skin, potentially informing new strategies against antibiotic-resistant bacterial infections by understanding the dynamics of local granulopoiesis. Long-term, the findings of this project may launch further investigations where autologous patient HSPCs can be extracted, isolated, and therapeutically used in at-risk patients. This project is complemented by a robust training plan designed to enhance my expertise in immunology, dermatology, and translational medicine. This comprehensive approach will not only facilitate the project's success but also aid my transition to become an independent researcher. The university's abundant resources for professional and educational development will be instrumental in achieving these objectives.
