Lymphatic Radiobiology

淋巴放射生物学

• 批准号: 7686725
• 负责人: TIMOTHY P PADERA
• 金额: $ 14.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-12 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686725
• 关键词: Address; Adenovirus Vector; Adenoviruses; Advocate; Affect; Aftercare; Animal Model; Apoptotic; Area; Arts; Award; Axilla; Axillary Lymph Node Dissection; Biochemistry; Biological Assay; Biology; Bite; Blood; Caliber; Cancer Patient; Cell Death; Cell division; Cells; Cessation of life; Commit; Complement; Complication; Data; Dermal; Development; Dose; Ear; Endothelial Cells; Engineering; Exposure to; Faculty; Failure; Fibroblast Growth Factor 2; Funding Opportunities; Future; General Hospitals; Goals; Growth; Growth Factor; Growth Factor Receptors; Human; Imaging technology; Immunohistochemistry; In Vitro; Incidence; Incubated; Infection; Institutes; Ionizing radiation; K-Series Research Career Programs; Kinetics; Knowledge; Laboratories; Lead; Leg; Light; Lymphangiogenesis; Lymphangiography; Lymphatic; Lymphatic Endothelial Cells; Lymphatic vessel; Lymphedema; Malignant Neoplasms; Massachusetts; Measures; Mediating; Mentors; Mentorship; Methods; Mitosis; Mitotic; Molecular; Molecular Biology; Molecular Target; Monitor; Mus; Nature; Necrosis; Neoplasm Metastasis; Neuropilin-1; Neuropilin-2; Operative Surgical Procedures; Pain; Pathway interactions; Patients; Phase; Positioning Attribute; Pre-Clinical Model; Prevention; Prior Therapy; Proliferating; Radiation; Radiation Tolerance; Radiation induced damage; Radiation therapy; Radiation-Sensitizing Agents; Radiobiology; Relative (related person); Research; Research Activity; Research Personnel; Research Training; Resources; Risk; Secure; Seeds; Signal Pathway; Signal Transduction; Signaling Molecule; Staining method; Stains; Swelling; Techniques; Technology; Testing; Therapeutic; Tissues; Training; United States; Universities; Vascular Endothelial Cell; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Venous; Woman; Work; cancer cell; career; design; experience; fibroblast growth factor receptor 3; genetic manipulation; in vitro Model; in vivo; inhibitor/antagonist; intravital microscopy; irradiation; knowledge base; lymph flow; malignant breast neoplasm; medical schools; novel; prevent; programs; radiation effect; repaired; research study; response; senescence; skills; small hairpin RNA; success; time use; tool; treatment planning

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.

描述（由申请人提供）：乳腺癌患者手术后的腋窝放射通常会导致水肿，这影响了美国近40万名妇女。淋巴水肿是毁容，疼痛，并形成一个病灶的感染。由于目前的治疗对许多患者几乎没有缓解，因此开发预防和逆转水肿形成的方法至关重要。使用淋巴管生成因子刺激淋巴管生长和逆转水肿已被提倡。然而，在癌症患者中，这种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，我们在这个独立之路奖中专注于水肿的预防。 虽然有关于许多组织对辐射敏感性的资料，但辐射对淋巴管的影响基本上没有报道。在这个建议中，我们将研究淋巴管内皮细胞的辐射敏感性和它们的细胞和分子对辐射的反应（目标1，指导阶段）。然后，我们将通过暴露于生长因子或生长因子信号转导的遗传操作来改变淋巴管内皮细胞的放射敏感性（目的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，独立期）。最后，我们将通过给予淋巴生长因子受体抑制剂来预防辐射诱导的淋巴管生成血管损伤（目的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，以预防患者的水肿。 我将在Brian Seed博士（导师）和Kathy Held博士（共同导师）的指导下完成马萨诸塞州总医院的导师阶段。我将利用这一指导阶段，以加强我的分子生物学和生物化学，放射生物学，我的导师各自的专长知识。在此期间，我将拥有E. L的资源。斯蒂尔实验室和我的导师们提供的机会，以及在哈佛大学、哈佛医学院和马萨诸塞州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，并将帮助我过渡到一个成功的独立学术研究。我将确保一个独立的教师职位的独立期间，这个奖项。在此期间，我还将积极寻求其他资助机会，以支持淋巴生物学和癌症转移方面的其他研究活动。在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疗后出现水肿。淋巴水肿治疗通常旨在控制肿胀并最大限度地减少与淋巴水肿相关的疼痛，但这些治疗方法仅略微有效。了解淋巴管对辐射的反应将有助于设计预防乳腺癌患者水肿形成的策略。