Mitigation of lymphatic injury by retinoic acid therapyin a large animal model

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，免疫功能低下。 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、毁容和复发性威胁肢体的感染的风险而导致生活质量差。在 在美国，水肿是治疗恶性肿瘤的淋巴结清扫术最常见的结果 如乳房或盆腔肿瘤。一旦确定，这种疾病是渐进的，很难治疗。 先前证明在淋巴损伤时给予9-顺式视黄酸（9-cisRA）可以 刺激淋巴管生成和减轻小鼠疾病进展。将这些发现转化为 临床环境涉及在第二个非啮齿动物大型动物模型中证明功效。为了解决这一问题， 我们选择猪是因为它的软组织解剖学和生理学与人类更相似 比啮齿动物模型更好。虽然该提案的中心目标是确定9-顺式RA是否可以预防 本提案的两个具体目标包括目标1：确定 9-顺式RA对猪严重淋巴损伤后肢体体积、MRI特征和淋巴转运的影响;以及 目的2：观察9-顺式维甲酸（9-cis RA）对大鼠脑缺血再灌注损伤后组织病理学和分子生物学变化的影响。 猪的严重淋巴损伤。完成这一建议将产生高度相关和可翻译的调查结果 这将有助于开发基于9-顺式RA的治疗方法，以预防和管理 继发性水肿。

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 malignancies such as breast or pelvic tumors. Once established, this disease is progressive and difficult to treat. We have previously demonstrated that administration of 9-cis retinoic acid (9-cis RA) at the time of lymphatic injury can stimulate lymphangiogenesis and mitigate disease progression in mice. A critical step in translating these findings to the clinical setting involves demonstrating efficacy in a second, non-rodent, large animal model. To address this, we have chosen swine due to the fact that it has soft tissue anatomy and physiology that is more similar to human than rodent models. While the central goal of this proposal will be to determine if 9-cis RA can prevent postsurgical lymphedema in swine, the two specific aims of this proposal include Aim 1: To determine the effect of 9-cis RA on limb volume, MRI characteristics, and lymphatic transport after critical lymphatic injury in swine; and Aim 2: To assess the effect of 9-cis RA on the histopathological and molecular changes in tissues at the site of critical lymphatic injury in swine. Completion of this proposal will yield highly relevant and translatable findings that will facilitate development of a 9-cis RA based therapeutic approach to prevention and management of secondary lymphedema in humans.