Retinoic Acid Induced Lymphangiogenesis for Post-surgical Lymphedema

淋巴水肿是一种无法治愈的疾病，其特征是淋巴阻塞，组织肿胀， 免疫功能障碍和淋巴损伤后的纤维化。淋巴水肿影响着500万美国人， 由于肢体残疾、毁容和复发风险， 威胁肢体的感染在美国，水肿是最常见的后果淋巴结转移 用于治疗实体瘤如乳腺癌或盆腔癌的解剖。尽管事实上 水肿是常见的和病态的，目前没有有效的药物治疗。使用 临床前啮齿动物模型的水肿，我们已经表明，9-顺式维甲酸（RA）显着 加速损伤后的淋巴再生，恢复功能性淋巴引流， 防止水肿的发展。我们的总体假设是RA介导的 淋巴管生成是一种有希望的治疗继发性水肿的方法。这项建议的目的， 这是在临床上实施这种治疗的第一个合乎逻辑的步骤， 了解RA调节淋巴管生成的机制， 这些化合物的用途的翻译框架。这项建议的具体目标包括： 目的1：确定RA如何选择性诱导淋巴管生成;目的2：阐明FGFR的作用 和VEGFR信号在RA介导的淋巴管生成中的作用;目标3：使用RA的早期生物标志物， 淋巴功能不全，以开发可指导RA治疗开始的预测模型。基于 目前缺乏有效的治疗方法，很明显，有必要制定一个病因为重点， 治疗术后水肿。拟议的研究将解决重要的机制 关于RA介导的淋巴管生成的问题，并开发基于 预测模型将指导RA治疗的治疗窗口。拟议的工作将 显著提高了我们对RA介导淋巴管生成的理解， 翻译的RA作为一种预防性治疗方案的手术后水肿。

Lymphedema is an incurable condition characterized by lymphatic obstruction, tissue swelling, immune dysfunction, and fibrosis after lymphatic injury. Lymphedema affects 5 million Americans 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 most commonly a consequence of lymph node dissection for the treatment of solid tumors such as breast or pelvic cancer. Despite the fact that lymphedema is common and morbid, there are currently no effective drug treatments. Using preclinical rodent models of lymphedema, we have shown that 9-cis retinoic acid (RA) significantly accelerates lymphatic regeneration following injury, restores functional lymphatic drainage, and prevents development of lymphedema. Our overarching hypothesis is that RA-mediated lymphangiogenesis is a promising therapy for secondary lymphedema. The objective of this proposal, which is the first logical step towards implementing this treatment clinically, is to increase our understanding of the mechanisms by which RAs regulate lymphangiogenesis and develop a translational framework for the use of these compounds. The specific aims of this proposal include Aim 1: Determine how RA selectively induces lymphangiogenesis; Aim 2: Elucidate the roles of FGFR and VEGFR signaling in RA-mediated lymphangiogenesis; and Aim 3: Use early biomarkers of lymphatic insufficiency to develop a predictive model that can guide initiation of RA therapy. Based on the current lack of effective therapy, it is clear that there is a need to develop an etiology-focused treatment for post-surgical lymphedema. The proposed studies will address important mechanistic questions regarding RA mediated lymphangiogenesis and also develop an early biomarker based predictive model that will guide treatment windows for RA therapy. The proposed work will significantly improve our understanding of RA-mediated lymphangiogenesis as well as support clinical translation of a RA as a preventative treatment regimen for post-surgical lymphedema.