Lymphatic Radiobiology

淋巴放射生物学

基本信息

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
项目类别：
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

项目摘要

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）：乳腺癌患者接受腋窝放射手术通常会导致淋巴水肿，影响美国近 400,000 名女性。淋巴水肿会毁容、疼痛并形成感染病灶。由于目前的治疗方法对许多患者的缓解效果甚微，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成因子来刺激淋巴管生长并逆转淋巴水肿。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，我们在独立之路奖中重点关注淋巴水肿的预防。虽然可以获得许多组织放射敏感性的信息，但放射对淋巴管的影响基本上没有报道。在本提案中，我们将研究淋巴内皮细胞的放射敏感性及其对辐射的细胞和分子反应（目标 1，指导阶段）。然后，我们将通过接触生长因子或对生长因子信号传导进行基因操作来改变淋巴内皮细胞的放射敏感性（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，我们将通过施用淋巴生长因子受体抑制剂来预防辐射引起的淋巴管生成损伤（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，以预防患者出现淋巴水肿。我将在马萨诸塞州总医院在 Brian Seed 博士（导师）和 Kathy Held 博士（共同导师）的指导下完成导师阶段。我将利用这个指导阶段来加强我对分子生物学、生物化学和放射生物学的知识，以及我的导师各自的专业知识。在此期间我将拥有 E.L. 的资源。斯蒂尔实验室和我导师的实验室，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员。我将在该奖项的独立期间获得独立教职职位。我还将积极寻求其他资助机会，以支持在此期间淋巴生物学和癌症转移方面的其他研究活动。到本奖项任期结束时，我打算建立一个强大的独立研究计划。相关性：美国有近 400,000 名乳腺癌患者在腋窝放疗后出现淋巴水肿。淋巴水肿治疗通常旨在控制肿胀并最大程度地减少与淋巴水肿相关的疼痛，但这些治疗的效果有限。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。