Retinoic Acid Induced Lymphangiogenesis for Post-surgical Lymphedema

淋巴水肿是一种不治之症，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， 与因肢体残疾、毁容和复发风险而导致的生活质量低下有关 威胁肢体的感染。在美国，淋巴水肿最常见的原因是淋巴结 用于治疗实体肿瘤的解剖，如乳腺癌或盆腔癌。尽管事实是 淋巴水肿是一种常见和病态的疾病，目前还没有有效的药物治疗。vbl.使用 临床前大鼠淋巴水肿模型的建立，我们已经证明9-顺式维甲酸(RA)显著 加速损伤后的淋巴再生，恢复功能性淋巴排泄，以及 防止淋巴浮肿的发展。我们的主要假设是RA介导的 淋巴管生成是治疗继发性淋巴水肿的一种有前景的治疗方法。这项提议的目标是， 这是临床上实施这种治疗的第一个合乎逻辑的步骤，就是增加我们的 了解RAS调节淋巴管生成和发展的机制 使用这些化合物的翻译框架。这项建议的具体目标包括 目的1：确定RA如何选择性地诱导淋巴管生成；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；以及目标3：使用早期生物标志物 淋巴供应不足，以开发可指导RA治疗开始的预测性模型。基座 在目前缺乏有效的治疗方法的情况下，显然有必要制定一种以病因学为重点的 手术后淋巴水肿的治疗。拟议的研究将解决重要的机制问题。 RA介导的淋巴管生成问题及其早期生物标志物的研究进展 将指导RA治疗的治疗窗口的预测性模型。拟议的工作将 显著提高我们对RA介导的淋巴管生成的理解，并为临床提供支持 将类风湿关节炎翻译为术后淋巴水肿的预防性治疗方案。

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.