Novel Mechanisms in the Resolution of Post-Surgical Lymphedema

项目摘要 这是一份有指导的临床科学家研究职业发展建议，适用于临床医生。 治疗手术后淋巴水肿，并正在接受培训，以成为一名独立的调查员。淋巴水肿结果 由淋巴功能障碍引起，以肢体肿大为特征。它最常见的原因是医源性的 在癌症外科治疗期间对淋巴系统继发的淋巴系统损伤(例如， 乳腺癌和黑色素瘤)。据估计，美国有500-1000万人患有淋巴水肿，2.5亿人 世界各地的人们都受到了影响。这种慢性疾病的发病率包括频繁的感染、疼痛和改变 功能。目前还没有治愈这种疾病的方法。管理包括压缩、切除程序、 以及显微外科手术、带血管的淋巴转移和淋巴静脉转流术。直播过程中， 患肢的淋巴管与静脉吻合以绕过损伤区域。手术是这样的 技术上具有挑战性、耗时，而且需要先进的设备。 三分之一的患者在淋巴清扫后出现淋巴水肿。在这些患者中有三分之二的人 未发生淋巴水肿，术后出现一过性肢体肿胀，可自行消退。类似地，一个 小鼠尾巴淋巴水肿模型可自发消肿。我们提出了一个新的假设 淋巴水肿诱导的自发性淋巴静脉分流和淋巴管生成导致生理性 淋巴水肿消退。我们使用淋巴水肿的小鼠尾巴模型来验证我们的假设。在目标1中，我们将 确定淋巴水肿自发消退的机制。此外，这项提案 提出了一种利用组织纳米转染技术(TNT)诱导淋巴静脉的创新方法 分流和淋巴管生成以改善淋巴水肿。在目标2中，我们假设TNT可以用来 局部地，通过靶向C型凝集素样受体(CLEC-)，局部传递基因货物以改善淋巴水肿。 2)、Syk和SLp76通路使淋巴管与静脉分离。诱导淋巴静脉分流将 类似于目前临床上用于治疗淋巴水肿的直播。 综上所述，这些实验将对识别自发淋巴的机制产生很大的影响 决议。建议的工作采用了一种新的方法来使用局部的、非全局的TNT来管理淋巴水肿 直接在受影响的地区。这位候选人是印第安纳大学的助理教授，致力于 成为一名内科科学家。他之前获得了翻译和临床研究的硕士学位 在哈佛医学院。候选人有多项试点和基金会资助，创业研究包， 专用实验室空间和40%的保护时间，在获得K08后将增加到75% 格兰特。有一个专家指导小组，包括外科副主席和应聘者司 主任，他们在指导内科科学家方面有充足的资金和经验。有强大的制度基础 承诺，这将有助于候选人向独立调查员过渡。

Project Summary This is a mentored clinical scientist research career development proposal for a junior physician who clinically treats post-surgical lymphedema and is training to become an independent investigator. Lymphedema results from lymphatic dysfunction and is characterized by limb enlargement. It is most commonly caused by iatrogenic injury to the lymphatic system secondary to lymph node excision during the surgical management of cancer (e.g, breast cancer and melanoma). It is estimated that 5-10 million Americans have lymphedema and 250 million people are affected worldwide. Morbidity from this chronic condition includes frequent infection, pain, and altered function. There is currently no cure for this disease. Management includes compression, excisional procedures, and microsurgical operations vascularized lymph node transfer and lymphovenous bypass (LVB). During LVB, lymphatics in the affected extremity are anastomosed to veins to bypass the injured area. The operation is technically challenging, time consuming, and requires advanced equipment. One-third of patients develop lymphedema following lymphadenectomy. The two thirds of those patients that do not develop lymphedema have transient postoperative limb swelling which resolves spontaneously. Similarly, a mouse tail model of lymphedema spontaneously resolves the swelling. We propose the novel hypothesis that lymphedema-induced spontaneous lymphovenous shunts and lymphangiogenesis lead to the physiological resolution of lymphedema. We use a murine tail model of lymphedema to test our hypothesis. In Aim 1, we will determine the mechanism responsible for spontaneous resolution of lymphedema. In addition, this proposal presents an innovative approach using tissue nanotransfection technology (TNT) to induce lymphovenous shunts and lymphangiogenesis to improve lymphedema. In Aim 2, we hypothesize that TNT can be used to topically, focally deliver genetic cargo to improve lymphedema by targeting the C-type lectin like receptor (CLEC- 2), Syk, and Slp76 pathways which keep lymphatics separated from veins. Inducing lymphovenous shunts would act similarly to LVB currently performed clinically to treat lymphedema. In summary, these experiments will be high impact in identifying the mechanism of spontaneous lymphatic resolution. The proposed work adopts a novel approach to managing lymphedema using focal, non-global TNT directly at the affected area. The candidate is an Assistant Professor at Indiana University who is dedicated to becoming a physician-scientist. He has obtained a previous Master’s degree in translational and clinical research at Harvard Medical School. The candidate has multiple pilot and foundation grants, a startup research package, dedicated laboratory space, and 40% protected time which will be increased to 75% upon obtaining the K08 grant. There is an expert mentorship panel, including the Vice-Chair of Surgery and the candidate’s Division Chief, who are well funded and experienced in mentoring physician scientists. There is strong institutional commitment which will facilitate the candidate transition to an independent investigator.