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

 描述(由申请人提供)：这份建议书概述了Homaira Rahimi博士的一个为期5年的培训计划，该计划将使她成为一名成功的儿科风湿病翻译研究员。Rahimi博士在罗格斯大学-新泽西医学院完成了内科/儿科住院医师学位，并在费城儿童医院完成了儿科风湿病研究员学位。她是罗切斯特大学的儿科学助理教授，在那里她从事炎症性关节炎的机制研究，并照顾患有青少年关节炎和其他自身免疫性疾病的儿童。这个K08奖项将为Rahimi博士提供专门的时间和指导，以扩展她在有效方案开发、全面数据分析和尖端实验室技术方面的技能。她将由爱德华·施瓦茨博士和克里斯托弗·里奇林博士指导，他们分别是骨科和风湿病领域的国际公认的领导者。施瓦茨博士是肌肉骨骼研究中心主任兼骨科教授。里奇林博士是过敏/免疫学和风湿科主任兼医学教授。他们是多产的调查人员，在指导方面有丰富的经验。这项研究计划针对类风湿性关节炎(RA)患者的关节炎发作，RA是一种慢性衰弱疾病。长期目标是了解类风湿性关节炎淋巴管功能障碍的病因，并评估淋巴管作为药物靶点改善疾病发作的潜力。目的是阐明炎性关节炎期间改变淋巴脉搏和淋巴流动的机制。初步证据表明，在淋巴组织中也发现了一氧化氮(NO)信号和参与血管扩张的NO受体可溶性鸟苷酸环酶(SGC)。因此，中央 假设通过sGC的NO信号在炎症过程中维持淋巴功能至关重要，选择性药物抑制是治疗RA急性发作的有效干预措施。这一假说将通过以下方式得到验证：1)检测主要的sGC亚单位(sGCβ1)是否在关节炎发作小鼠的腓淋巴结传入淋巴管平滑肌细胞中表达；2)证明sGCβ1对淋巴管收缩和体内外脉搏至关重要；3)证明sGCβ1是治疗关节炎发作的靶点，因为基因缺失和药物抑制可以缓解小鼠模型中的疾病。这项研究提案将填补有关关节炎发作中淋巴功能异常的病因的关键空白。通过将淋巴管作为改善疾病的一种新的治疗干预措施，这项研究具有提高慢性关节炎患者生活质量的强大潜力。

 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.