Regulation of HIF-1 and tumor angiogenesis by PML and PML-RARa

描述（由申请人提供）：本提案描述了一个为期五年的培训计划，用于发展癌症生物学的学术生涯。我作为一名分子生物学家在癌症研究方面有七年的工作经验，我现在计划通过利用实体瘤和白血病的小鼠模型来扩展我的技能。Pier Paolo Pandolfi博士是一位领先的癌症生物学家，他在体内癌症建模方面拥有丰富的经验，并培训了许多独立的研究人员。该计划将通过C博士的合作来丰富。科东-卡多，S医生。拉菲尔和C.西蒙该奖项的第一部分将在纪念斯隆-凯特琳癌症中心完成，这是一个卓越的科学环境，将提供所有必要的资源，以促进这一职业发展奖的成功。 研究将集中于研究早幼粒细胞白血病基因PML和急性早幼粒细胞白血病融合蛋白（API）PML RAR α对HIF-1和肿瘤血管生成的调控。 转录因子HIF-1是细胞对缺氧反应的主要调节因子。HIF-1在实体瘤中经常上调，并通过促进新血管生成促进肿瘤进展。相反，PML在实体瘤中经常丢失。我的初步观察表明PML是HIF-1的负调节因子。因此，当受到缺氧刺激时，Pml-/-细胞具有比野生型细胞更高的HIF-1活性，并且Pml-/-小鼠响应于缺血具有增加的新血管生成。最后，我发现PML-RAR α作为HIF-1的组成型转录共激活因子。这一观察结果支持了新的概念，即骨髓中的新血管生成是白血病发生的重要过程。 在这个建议中，我的目的是回答以下问题：PML调节HIF-1的分子机制是什么？PML缺失在实体瘤新生血管形成过程中的作用是什么？最后，HIF活性在APL的发展中重要吗？ 我将针对这些问题在以下具体目标：1.阐明PML对HIF-1 α调控的分子机制。研究PML缺失对肿瘤血管生成和肿瘤进展的影响; 3.在急性早幼粒细胞白血病小鼠模型中研究缺氧诱导因子-1 α在白血病中的作用。 本建议书中概述的培训计划将启动我的独立研究生涯。

DESCRIPTION (provided by applicant): This proposal describes a five-year training program for the development of an academic career in Cancer Biology. I have seven years experience as a molecular biologist working in cancer research and I am now planning to expand my skills by utilizing mouse models of solid tumors and leukemias. In the first part of the program, I will be mentored by Dr. Pier Paolo Pandolfi, a leading cancer biologist who has great experience in modeling cancer in vivo and who has trained numerous independent investigators. The program will be enriched by the collaboration of Dr. C. Cordon-Cardo, Dr. S. Rafii and Dr. C. Simon. The first part of the award will be completed at Memorial Sloan-Kettering Cancer Center, a scientific environment of excellence that will provide all the resources necessary to promote the success of this Career Development Award. Research will focus on the study of the regulation of HIF-1 and tumor angiogenesis by the promyelocytic leukemia gene PML, and the fusion protein of acute promyelocytyc leukemia (API), PML RARa. The transcription factor HIF-1 is the main regulator of cellular responses to hypoxia. HIF-1 is frequently upregulated in solid tumors and fosters tumor progression by promoting neoangiogenesis. Conversely, PML is frequently lost in solid tumors. My preliminary observations indicate that PML is a negative regulator of HIF-1. Accordingly, Pml-/- cells have higher HIF-1 activity than wild-type cells when subjected to hypoxic stimuli and Pml-/- mice have increased neoangiogenesis in response to ischemia. Finally, I have found that PML-RARa acts as a constitutive transcriptional co-activator of HIF-1. This observation supports the novel concept that neoangiogenesis in the bone marrow is an important process in leukemogenesis. In this proposal, I aim at answering the following questions: What is the molecular mechanism by which PML regulates HIF-1? What is the effect of PML loss in the process of neoangiogenesis in solid tumors? And, finally, is HIF activity important in the development of APL? I will address these questions in the following specific aims: 1. Elucidate the molecular mechanisms of HIF-1 a regulation by PML; 2. Study the effect of PML loss on tumor angiogenesis and tumor progression in vivo; 3. Study the role of HIF-1a overexpression in leukemia in mouse models of APL. The Training Program outlined in this proposal will launch my independent research career.