Lymphatic Radiobiology

描述(申请人提供)：乳腺癌患者手术后的腋窝放射经常会导致淋巴水肿，这在美国影响到近40万女性。淋巴水肿是毁容的，疼痛的，并形成感染的病灶。由于目前的治疗方法对许多患者几乎没有缓解作用，因此开发预防和逆转淋巴水肿形成的方法至关重要。人们提倡使用淋巴管生长因子来刺激淋巴管生长和逆转淋巴水肿。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，我们把重点放在淋巴水肿的预防上，这是独立之路奖的重点。 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在很大程度上还没有报道。在这项提案中，我们将研究淋巴管内皮细胞的辐射敏感性以及它们对辐射的细胞和分子反应(目标1，指导阶段)。然后，我们将通过暴露于生长因子或对生长因子信号的遗传操作来改变淋巴管内皮细胞的辐射敏感性(目标2，独立阶段)。我们将通过测量体内正常和增殖淋巴管的放射敏感性来补充这些研究(目标3，独立阶段)。最后，我们将通过使用淋巴生长因子受体的抑制剂来预防辐射导致的淋巴管损伤(目标3，独立阶段)。该项目的最终目标是确定保护淋巴管免受辐射损伤的策略，以防止患者出现淋巴水肿。 我将在布赖恩·塞德博士(导师)和凯西·赫尔德博士(共同导师)的指导下，在马萨诸塞州综合医院完成导师阶段。我将利用这个指导阶段来加强我对分子生物学和生物化学以及放射生物学的知识，这些都是我的导师们各自的专长。在此期间，我将获得E.L.斯蒂尔实验室和我导师的资源，以及哈佛大学、哈佛医学院和麻省理工学院的许多教育和培训机会。我的导师致力于我的职业发展，并将帮助我转变为一名成功的独立学术研究人员。我将在该奖项的独立期内获得一个独立的教员职位。在此期间，我还将积极寻求其他资助机会，以支持更多淋巴生物学和癌症转移方面的研究活动。到这个奖项的任期结束时，我打算建立一个强大的独立研究计划。 相关性：在美国，近40万乳腺癌患者在腋窝放射后出现淋巴水肿。淋巴浮肿的治疗通常是为了控制肿胀并将与淋巴浮肿相关的疼痛降至最低，但这些治疗方法只是略微有效。了解淋巴管对辐射的反应将有助于设计预防乳腺癌患者淋巴水肿形成的策略。

DESCRIPTION (provided by applicant): 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 moecular response to radiation (Aim 1, Mentored Phase). We will then alter lymphatic endothelial cell radiosensitivity through exposure to growth factors or genetic manipulation of growth factor signaling (Aim 2, Independent Phase). We will complement these studies by measuring the radiosensitivity of normal and proliferating lymphatic vessels in vivo (Aim 3, Independent Phase). Finally, we will prevent radiation induced damage of lymphangiogenic vessels by administering inhibitors of lymphatic growth factor receptors (Aim 3, Independent Phase). 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 the Mentored Phase at Massachusetts General Hospital under the guidance of Dr. Brian Seed (Mentor) and Dr. Kathy Held (Co-mentor). I will use this Mentored Phase to strengthen my knowledge of molecular biology and biochemistry, and radiobiology, the respective expertises of my mentors. During this period I will have the resources of the E.L. Steele Laboratory and those of my mentors available, as well as many educational and training opportunities at Harvard University, Harvard Medical School and Massachusetts Institute of Technology. My mentors are committed to the development of my career and will help my transition into a successful independent academic researcher. I will secure an independent faculty position for the Independent Period of this Award. I will also vigorously pursue other funding opportunities to support additional research activities in lymphatic biology and cancer metastasis during this period. By the end of the term of this Award, I intend to have established a strong independent research program. Relevance: Nearly 400,000 breast cancer patients in the United States develop lymphedema after axillary radiation. Lymphedema treatments are generally designed to control swelling and minimize the pain associated with lymphedema, but these treatments are only marginally effective. Understanding the response of lymphatic vessels to radiation will help design strategies to prevent lymphedema formation in breast cancer patients.