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 淋巴损伤后的功能障碍和纤维化。淋巴水肿影响了500万美国人，并与 由于四肢残疾、毁容和复发性威胁肢体感染的风险，生活质量较差。在……里面 在美国，淋巴水肿最常见的原因是为了治疗恶性肿瘤而清扫淋巴。 例如乳房或骨盆肿瘤。一旦确诊，这种疾病是进行性的，很难治疗。我们有 先前证明，在淋巴损伤时给予9-顺式维甲酸(9-顺式维甲酸)可以 刺激小鼠淋巴管生成，减缓疾病进展。翻译这些发现的关键一步 对临床环境的研究包括在第二个非啮齿动物大型动物模型中展示疗效。为了解决这个问题， 我们之所以选择猪，是因为它的软组织解剖学和生理学更接近人类 而不是啮齿动物模型。虽然这项提案的中心目标将是确定9-cis RA是否可以防止 这项建议的两个具体目标包括目标1：确定 9-顺式维甲酸对猪严重淋巴损伤后肢体体积、MRI特征和淋巴转运的影响 目的：探讨9-顺式维甲酸对大鼠脑缺血再灌注损伤局部组织病理学和分子水平的影响。 猪的严重淋巴损伤。完成这项提案将产生高度相关和可翻译的结果 这将促进基于9-顺式维甲酸的治疗方法的发展，以预防和管理 人类继发性淋巴水肿。

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.