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

 描述（由申请人提供）：本提案概述了Homaira Rahimi博士的5年培训计划，该计划将使她能够作为儿科风湿病学的翻译研究者成功发展职业生涯。Rahimi博士在罗格斯大学新泽西医学院完成了内科/儿科住院医师培训，并在费城儿童医院获得了儿科风湿病学奖学金。她是罗切斯特大学的儿科助理教授，在那里她从事炎症性关节炎的机制研究，并照顾青少年关节炎和其他自身免疫性疾病的儿童。这个K 08奖项将为Rahimi博士提供专门的时间和指导，以扩展她在有效的方案开发，综合数据分析和尖端实验室技术方面的技能。Edward施瓦茨博士和Christopher Ritchlin博士将分别指导她，他们是骨科和流变学领域的国际公认领导者。施瓦茨博士是肌肉骨骼研究中心主任和骨科教授。Ritchlin博士是过敏/免疫学和流变学系主任和医学教授。他们是多产的调查员，在指导方面有着丰富的经验。本研究项目针对类风湿关节炎（RA）患者的关节炎发作，这是一种慢性衰弱性疾病。长期目标是了解RA淋巴管功能障碍的病因，并评估作为药物靶点的药物缓解疾病发作的潜力。目的是阐明在炎症性关节炎期间改变淋巴脉冲和流动的机制。初步证据表明，一氧化氮（NO）信号传导和NO受体可溶性鸟苷酸环化酶（sGC），这是参与血管系统中的血管舒张，也发现在淋巴组织。因此，中央 假设是通过sGC的NO信号传导对于在炎症期间维持淋巴功能是关键的，并且选择性药物抑制是治疗RA发作的有效的、有效的干预。该假设将通过以下方式进行检验：1）检查显性sGC亚基（sGCβ1）是否在关节炎发作小鼠的腘淋巴结传入淋巴平滑肌细胞中表达; 2）显示sGCβ1对淋巴管收缩和离体和体内脉冲至关重要; 3）证明sGCβ1是关节炎发作的治疗靶点，因为基因删除和药物抑制改善了鼠模型中的疾病。这项研究建议将填补一个关键的差距，关于关节炎发作异常淋巴功能的病因。通过将关节炎药物作为一种改善疾病的新的治疗干预手段，这项研究有很大的潜力来改善慢性关节炎患者的生活质量。

 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.