Semaphorin 3F: Structure, Function, and Anti-Metastatic Activity

描述（由申请人提供）：候选人Diane Bielenberg博士是儿童医院和哈佛医学院外科研究部的讲师，由血管生成研究领域的先驱Judah Folkman博士担任主任。作为血管生物学项目的一部分，癌症生物学家Bielenberg博士专门研究转移，即恶性肿瘤细胞从身体的一个部位扩散到另一个部位。申请人的长期职业目标是继续从事学术研究，并继续研究癌症转移和血管生成的生物学。大多数癌症患者死于转移，只有通过了解这一过程的生物学，我们才能希望开发出更好的工具来对抗这种疾病。Bielenberg博士之前研究了干扰素抗血管生成治疗的分子机制，内源性干扰素- β在皮肤婴儿血管瘤复发中的作用，以及血管内皮生长因子的天然可溶性受体可溶性神经匹林的鉴定和抗肿瘤活性。自从被提升为讲师以来，Bielenberg博士一直专注于研究一种名为Semaphorin 3F的新型转移抑制因子。Semaphorin 3F在肺癌中普遍缺失，是一种假定的肿瘤抑制基因，但最近Bielenberg博士和她的导师Michael Klagsbrun博士发现，在许多肿瘤细胞系中，Semaphorin 3F与转移呈负相关。当Semaphorin 3F在转移细胞中表达时，肿瘤显著地恢复到良性、低血管和包封的肿瘤表型。这项K01研究计划将继续这一令人兴奋的发现，并专注于Semaphorin 3F抗转移作用的分子机制。我们假设Semaphorin 3F将调节转移级联的关键步骤，包括血管生成和淋巴管生成，并可能为转移性疾病患者提供新的治疗策略。K01奖将通过提供包括蛋白质工程和蛋白质纯化在内的生物化学领域的额外培训，以及促进更多的合作和参与区域和国家会议，促进该候选人从讲师转变为哈佛医学院外科研究部的独立研究者。最重要的是，霍华德·特明奖将使这项研究项目朝着长期稳定疾病的最终目标继续下去。

DESCRIPTION (provided by applicant): The candidate, Dr. Diane Bielenberg, is an instructor in the Surgical Research Division at Children's Hospital and Harvard Medical School, chaired by Dr. Judah Folkman, the pioneer of the field of angiogenesis research. As part of the Vascular Biology Program, Dr. Bielenberg, a cancer biologist, has specialized in studies of metastasis, the spread of malignant tumor cells from one site in the body to another. The longterm career goals of the applicant are to remain in academic research and continue to study the biology of cancer metastasis and angiogenesis. Most cancer patients die from metastasis, and only by understanding the biology of this process can we hope to develop better tools to fight this disease. Dr. Bielenberg has previously studied the molecular mechanisms involved in anti-angiogenesis therapy by interferons, the role of endogenous interferon-beta in the involution of cutaneous infantile hemangiomas, and the identification and anti-tumor activity of a natural soluble receptor for vascular endothelial growth factor called soluble neuropilin. Since being promoted to an instructor, Dr. Bielenberg has focused on a novel suppressor of metastasis, called Semaphorin 3F. Semaphorin 3F is commonly deleted in lung cancer and is a putative tumor suppressor gene, but recently Dr. Bielenberg and her mentor, Dr. Michael Klagsbrun, have shown that Semaphorin 3F is inversely correlated with metastasis in many tumor cell lines. When Semaphorin 3F was expressed in metastatic cells, the tumors remarkably reverted to a benign, hypo-vascular and encapsulated tumor phenotype. This K01 research proposal will follow-up this exciting finding and focus on the molecular mechanisms responsible for the anti-metastatic effect of Semaphorin 3F. We hypothesize that Semaphorin 3F will regulate key steps in the metastatic cascade including angiogenesis and lymphangiogenesis and may offer a novel therapeutic strategy for patients with metastatic disease. A K01 award would facilitate the transition of this candidate from instructor to an independent investigator in the Department of Surgical Research at Harvard Medical School by providing additional training in areas of biochemistry including protein engineering and protein purification, as well as enabling additional collaborations and participation in regional and national meetings. Most of all, a Howard Temin Award would enable the continuation of this research project toward the ultimate goal of long-term stable disease.