Bcl-2 dependent fibroblast resistance to apoptosis occurs through persistent IL-6 signaling

PROJECT SUMMARY This proposal describes a five-year project through which Dr. Joseph Cooley will develop the skills and knowledge necessary to transition into an independent basic and translational physician-scientist. He will receive mentorship from a primary mentor, several advisors and collaborators from National Jewish Health and the

University of Colorado. His long-term career goal is to help patients with fibrotic lung diseases by uncovering mechanisms of progressive pulmonary fibrosis (PPF) and developing therapeutic strategies to halt or reverse fibrosis. This proposal explores how interleukin-6 (IL-6) promotes apoptosis resistance in fibroblasts by

increasing expression of the anti-apoptotic protein BCL-2, and how this IL-6-BCL-2 axis can be targeted

therapeutically. It is directly relevant to the NHLBI given its applicability to all progressive fibrosing interstitial lung diseases (ILDs). Candidate: Joseph Cooley, DO is board certified in Internal, Pulmonary, and Critical Care Medicine. He is an Instructor at National Jewish Health in Denver, CO who clinically specializes in ILD and

performs rigorous basic and translational scientific investigations related to pulmonary fibrosis as a physician- scientist. Training: Dr. Cooley has created an extensive career development plan that builds on his prior mentored research during medical school, residency, and fellowship training. His multi-faceted career

development plan utilizes formal classwork, conferences, seminars, workshops, small and large group collaborative meetings, and on-on-one training to develop and expand his skills and knowledge of 1) biologic concepts related to mechanisms of cell death, biostatistics, genetics and genomics, and lung injury, repair and

fibrosis, 2) laboratory techniques, 3) scientific writing, 4) rigorous experimental design, 5) data interpretation, 6) oral presentation, and 7) leadership, mentorship and laboratory management. Mentor/Environment: Dr. Cooley’s primary mentor is Dr. Elizabeth Redente, PhD whose laboratory has a history of producing high-impact

research regarding fibroblasts behavior during lung injury, repair and fibrosis. Dr. Cooley has assembled a team of mentors and collaborators that are experts in pertinent aspects of the project including advanced genomic analysis techniques (Dr. Gerber), cutting edge gene transfer techniques using viral vectors (Dr. Bridges),

genetics and genomics of pulmonary fibrosis (Dr. Schwartz), and IL-6 signaling across diverse disease states (Dr. Rincon). All proposed activities will be performed at National Jewish Health, a highly collaborative top-ranked research institution. Research Project: The primary objective of this proposal is to determine if fibroblast BCL-

2 dependent apoptosis resistance is driven by sustained IL-6 signaling in PPF, and if this IL-6-BCL-2 axis can be targeted therapeutically to treat PPF. We will use in vitro cell culture and precision cut lung slices from humans and mice, and in vivo mouse models to determine 1) the effects of IL-6 on BCL-2 expression in fibroblasts during

PPF, 2) the causal role of IL-6 in driving PPF and 3) ability of IL-6 signaling inhibition or genetic knockout to reduce BCL-2 expression in fibroblasts, induce fibroblast apoptosis and reverse established PPF.