This proposal describes a five-year mentored training program for the career development of a physician- scientist to examine how physiologic stress pathways induced by catecholamines and glucocorticoids regulate cutaneous immunity to pathogens. Currently, little is known about how transcriptional networks elicited by these stress molecules globally regulate inflammatory responses to cutaneous pathogens in humans. Using high throughput RNA sequencing, this proposal will allow the investigation of how catecholamine- or glucocorticoid-induced transcriptional networks intersect with Toll-like receptor (TLR)-induced inflammatory pathways. This network analysis will be applied to skin lesions of leprosy patients to analyze their contribution to leprosy pathogenesis. Finally, the effects of stress molecules on T cell polarization and antimicrobial responses to M. leprae will be determined as it is a cutaneous pathogen whose control is dependent on appropriate TLR-mediated immunity. This project addresses several goals of NIAMS including how neural inputs control cutaneous inflammatory and host defense pathways in macrophages, and how they regulate T cell polarization and antimicrobial pathways in leprosy. The candidate previously completed a PhD studying the generation of adaptive immune responses in murine sepsis and will have completed both clinical residency training and a post-doctoral fellowship through the STAR program research track at UCLA. Through this proposal, he will develop new molecular techniques, including high throughput RNA sequencing and the computational analytical skills required to understand transcriptional regulation, restriction enzyme-based promoter accessibility studies, and chromatin histone immunoprecipitation to increase his molecular skills. He will also expand his clinical translational skills, as this proposal has a large translational component involving healthy controls and leprosy patients. These new techniques and skills can be applied to virtually any skin disorder. This critical mentored phase of training will be performed under the mentorship of Stephen Smale, PhD, an expert in the field of transcriptional regulation of immune responses, and Robert Modlin, MD, a pioneer in translational cutaneous immunology research, both of whom have trained numerous independent investigators. Additionally, these two PIs are collaborators on UCLA's NIAMS-funded P50 Center for Research Translation in skin disease, and will be able to provide additional support through their existing collaboration. The K08 award will allow the investigation of this research in the context of a much larger goal. This research will improve the understanding of how inflammatory transcriptional networks are regulated by physiologic stress pathways in the skin and provide insight into potential therapeutics for cutaneous immunity. This program will allow the candidate to develop the skills and tools needed to embark upon this research project, while having the necessary mentorship and support needed towards the goal of maturing into an independent investigator.
Glucocorticoids and catecholamines, two key mediators of physiologic stress, have long been known to impact innate and adaptive immune responses. The impact of these key mediators of physiologic stress on immunity to cutaneous pathogens in humans has not been investigated in detail. By understanding how transcriptional networks activated by stress molecules and Toll-like receptor-mediated immunity intersect, and how the downstream mechanisms utilized by stress molecules modulate immunity, we hope to uncover how physiologic stress impacts cutaneous immunity in leprosy and develop targeted therapies that mitigate the impact of stress on immune-mediated dermatoses.
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