Investigation of 9-cis Retinoic Acid as a Novel Treatment for Post-Surgical Lymphedema

项目总结/摘要 淋巴水肿是一种无法治愈的疾病，其特征是淋巴损伤后的组织肿胀。它影响了 全世界有1.4亿人，由于肢体残疾， 毁容和复发性威胁肢体的感染的风险。在美国，水肿通常是由于淋巴 淋巴结切除术与恶性肿瘤（如乳腺或盆腔肿瘤）的治疗相关。有 目前还没有已知的医学疗法可以预防或逆转慢性疼痛患者的水肿的临床进展， 人类然而，最近的数据表明，手术转移血管化淋巴结（VLN），以取代 受损的淋巴结或转移淋巴流从远端肢体可以限制甚至逆转疾病 进展由于淋巴损伤和回流是水肿的根本原因，我们假设， 在起始淋巴损伤时外源性刺激淋巴管生成可能是有效的 预防和/或治疗水肿的策略。我们以前已经证明，9-顺式视黄酸（9-顺式 RA）在体外可促进淋巴管生成，在体内可限制水肿。具体目标是 目的：1）阐明9-cis RA减少手术诱导的高血压的作用机制 2）确定9-cis RA预防后水肿所需的最小有效剂量（MED）。 探讨9-顺式维甲酸对带血管蒂淋巴结瓣移植的影响 使用一种新的转基因荧光淋巴报告大鼠。我们希望这些研究的数据能够支持 快速转化为人类临床试验，特别是因为9-顺式RA（阿利维A酸）已经获得FDA批准。数据 从这个建议有可能重新目的9-顺式RA作为第一个药理学药物， 显著影响继发性水肿的发作和进展。校长Alex Wong博士 这项补助金的调查员是一名外科医生兼科学家，他的长期目标是成为一名独立的 研究人员在该领域的水肿。他的目标是成为风湿性关节炎治疗的专家， 领导使用RA和其他模式的临床试验。Young-Kwon Hong博士是这方面的主要导师 格兰特是淋巴管生成和水肿的国际专家。他是一名知名的调查员， NIH R系列资金，并在指导博士和MD科学家独立方面有着坚实的记录。的 建议的职业发展计划，结合科学调查，正式的课程工作，并经常 评估科学进展的会议对王博士实现独立的目标至关重要。

Project Summary/Abstract Lymphedema is an incurable condition characterized by tissue swelling after lymphatic damage. It affects over 140 million individuals worldwide and is associated with poor quality of life due to extremity disability, disfigurement, and risk for recurrent limb-threatening infection. In the US, lymphedema is usually due to lymph node resection in association with the treatment of malignancies such as breast or pelvic tumors. There are currently no known medical therapies that can prevent or reverse the clinical progression of lymphedema in humans. However, recent data suggests that surgical transfer of vascularized lymph nodes (VLN) to replace damaged lymph nodes or divert lymphatic flow from a distal extremity may limit and even reverse disease progression. Since lymphatic damage and backflow is the root cause of lymphedema, we hypothesize that exogenous stimulation of lymphangiogenesis at the time of the initiating lymphatic injury may be an effective strategy to prevent and/or treat lymphedema. We have previously demonstrated that 9-cis retinoic acid (9-cis RA) can promote lymphangiogenesis in vitro and can limit lymphedema in vivo. The specific aims of this proposal are: 1) To elucidate the mechanism by which 9-cis RA acts to minimize surgically induced lymphedema in vivo; 2) To determine the minimal effective dose (MED) of 9-cis RA necessary to prevent post- surgical lymphedema; and 3) To determine effect of 9-cis RA on vascularized lymph node flap transfers (VLN) using a novel transgenic fluorescent lymphatic reporter rat. We expect data from these studies to support rapid translation to human clinical trials, especially since 9-cis RA (Alitretinoin) is already FDA approved. Data from this proposal has the potential to re-purpose 9-cis RA as the first pharmacologic agent used to significantly impact the onset and progression of secondary lymphedema. Dr. Alex Wong, the principal investigator of this grant, is a surgeon-scientist who has a long-term goal of becoming an independent investigator in the field of lymphedema. He goal is to become an expert in RA therapy for lymphedema and lead clinical trials using RA and other modalities. Dr. Young-Kwon Hong, PhD is the primary mentor for this grant, is an international expert in lymphagiogenesis and lymphedema. He is an established investigator with NIH R-series funding and has a solid track record in mentoring PhD and MD scientists to independence. The proposed career development plan that integrates scientific investigation, formal course work, and frequent meetings to assess scientific progression will be essential for Dr. Wong's goals towards independence.