sGC beta1: A Potential Critical Regulator of the Lymphatic Pulse and Novel Target in Arthritic Flare

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 DESCRIPTION (provided by applicant): This proposal outlines a 5-year training program for Dr. Homaira Rahimi that will allow her to develop a successful career as a translational investigator in pediatric rheumatology. Dr. Rahimi completed an Internal Medicine/Pediatrics residency at Rutgers University-New Jersey Medical School and fellowship in Pediatric Rheumatology at The Children's Hospital of Philadelphia. She is an Assistant Professor in Pediatrics at The University of Rochester, where she is engaged in mechanistic studies of inflammatory arthritis and cares for children with juvenile arthritis and other autoimmune conditions. This K08 award will provide Dr. Rahimi the dedicated time and mentorship to expand her skills in effective protocol development, comprehensive data analysis, and cutting edge laboratory techniques. She will be mentored by Drs. Edward Schwarz and Christopher Ritchlin, internationally recognized leaders in their fields of Orthopedics and Rheumatology, respectively. Dr. Schwarz is the Director of the Center for Musculoskeletal Research and Professor in Orthopaedics. Dr. Ritchlin is Chief of the Division of Allergy/ Immunology and Rheumatology and Professor of Medicine. They are prolific investigators, with extensive experience in the mentorship. This research program addresses arthritic flare in patients with rheumatoid arthritis (RA), a chronic debilitating condition. The long-term goal is to understand the etiology of lymphatic vasculature dysfunction in RA and evaluate the potential of the lymphatics as a drug target to ameliorate disease flare. The objective is to elucidate the mechanisms that alter the lymphatic pulse and flow during inflammatory arthritis. Preliminary evidence demonstrates that nitric oxide (NO) signaling and the NO receptor soluble guanylyl cyclase (sGC), which is involved in vasodilation in blood vasculature, is also found in lymphatic tissue. Thus, the central hypothesis is that NO signaling through sGC is critical to maintaining lymphatic function during inflammation, and selective drug inhibition is an effective, valid intervention to treat RA flare. This hypothesis will be tested by 1) examining if the dominant sGC subunit (sGCβ1) is expressed in lymphatic smooth muscle cells afferent to the popliteal lymph node in mice with arthritic flare 2) showing that sGCβ1 is critical for lymphatic vessel contraction and pulse ex vio and in vivo and 3) proving that sGCβ1 is a therapeutic target for arthritic flare, as gene deletio and drug inhibition ameliorates disease in murine models. This research proposal will fill a critical gap regarding the etiology of aberrant lymphatic function in arthritic flare. By targetingthe lymphatics as a novel therapeutic intervention in ameliorating disease, this research has strong potential to improve the quality of life for patients with chronic arthritis.