Lymphatic Radiobiology

乳腺癌患者手术时的腋窝放疗经常会导致淋巴水肿，影响到近 美国有40万名女性。淋巴水肿是毁容的，疼痛的，并形成感染的病灶。AS 目前的治疗方法对许多患者几乎没有缓解作用，关键是要找到预防和治疗的方法 逆转淋巴水肿的形成。淋巴管生成生长因子在淋巴生长中的应用 并提倡逆转淋巴水肿。然而，在癌症患者中，这一策略可能会促进 癌细胞的进一步扩散。为了避免这种并发症，我们将重点放在淋巴水肿的预防上 独立之路奖。 虽然关于许多组织的辐射敏感性的信息是可用的，但辐射对淋巴管的影响 船只基本上没有上报。在这项建议中，我们将研究淋巴管的辐射敏感性。 内皮细胞及其对辐射的细胞和分子反应。然后我们会改变淋巴 内皮细胞对生长因子的辐射敏感性或生长因子的基因操作 发信号。我们将通过测量正常和增殖期的放射敏感性来补充这些研究。 体内的淋巴管。最后，我们将通过以下措施防止辐射导致的淋巴管损伤 注射淋巴生长因子受体的抑制剂。这个项目的最终目标是确定 保护淋巴管免受辐射损伤的策略，以防止淋巴水肿 病人。 我将在IVIassachusetts综合医院的E.L.斯蒂尔实验室完成这项工作，该医院有 建议的实验所需的适当的动物设施和活体成像设备。我的 导师布莱恩·塞德博士和凯瑟琳·赫尔德博士将继续在这个项目上与我合作，并 致力于我的事业发展，并将帮助我过渡到一个成功的独立 学术研究人员。

Axillary radiation with surgery in breast cancer patients often leads to lymphedema, which affects nearly 400,000 women in the United States. Lymphedema is disfiguring, painful and forms a nidus for infection. As current treatments provide little relief for many patients, it is critical to develop methods to prevent and reverse the formation of lymphedema. The use of lymphangiogenic growth factors to spur lymphatic growth and reverse lymphedema has been advocated. However, in cancer patients this strategy may facilitate the further spread of cancer cells. To avoid this complication, we focus on lymphedema prevention in this Pathway to Independence Award. While information on the radiosensitivity of many tissues Is available, the effects of radiation on lymphatic vessels have been largely unreported. In this proposal we will study the radiosensitivity of lymphatic endothelial cells and their cellular and molecular response to radiation. We will then alter lymphatic endothelial cell radiosensitivity through exposure to growth factors or genetic manipulation of growth factor signaling. We will complement these studies by measuring the radiosensitivity of normal and proliferating lymphatic vessels In vivo. Finally, we will prevent radiation-induced damage of lymphangiogenic vessels by administering inhibitors of lymphatic growth factor receptors. The ultimate goal of this project is to identify strategies to protect lymphatic vessels from radiation-induced damage in order to prevent lymphedema in patients. I will complete this worl< in the E.L. Steele Laboratories at IVIassachusetts General Hospital, which has the approriate animal faciiities and intravital Imaging equipment necessary for the proposed experlmeints. My mentors, Drs. Brian Seed and Kathryn Held, will continue to collaborate with me on this project and are committed to the development of my career and will help my transition into a successful independent academic researcher.