Spatial and Temporal Regulation of Angiogenesis

血管生成的时空调节

• 批准号: 6851946
• 负责人: HAROLD FISHER DVORAK
• 金额: $ 32.51万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-13 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6851946
• 关键词: angiogenesis; blood vessels; clinical research; metastasis; neoplasm /cancer blood supply; thrombospondins; vascular endothelial growth factors

DESCRIPTION (provided by applicant): This program project focuses on the structure and function of tumor blood vessels from many angles: roles and functions of angiogenic cytokines and endogenous inhibitors in tumors and in surrogate tumor blood vessels, the gene expression induced by these factors and their role in tumor angiogenesis, and the impact of angiogenic cytokines and angiogenesis on tumor progression. This proposal outlines a series of experiments that focus on one of major signaling pathways downstream of the major angiogenic cytokines, the Akt pathway, as a mediator of many tumor blood vessel abnormalities: their large size, poor support, increased permeability and instability. Our preliminary data demonstrate that Akt signaling in physiological angiogenesis involves a very precise switching 'on' and 'off of the Akt signal. However, when this 'off switch is inhibited, the resulting vessels recapitulate many aspects of tumor blood vessels, vessels of other vascular anomalies and 'mother vessels', a term coined by Dr. Dvorak to describe blood vessels formed by overexpression of VEGF-A and other cytokines. This grant application seeks to explore the role of Akt in 'mother vessel'/'tumor vessel' formation, and the impact of downstream Akt targets on the individual features and functions of these abnormal blood vessels. We also propose to explore the mechanism behind our novel finding that TSP-1 modulates Akt signaling. This project is written for 3 years to enable it to fold into the existing funding schedule of this program project. Aims: 1. Test the hypothesis that upregulation of Akt activity is sufficient to recapitulate the structure and function of abnormal blood vessels reminiscent of tumor vessel in a non-tumor environment 2. Identify the downstream signaling pathways that mediate Akt affects 3. Explore the mechanisms of Thrombospondins on Akt signaling. COLLABORATING INSTITUTIONS (S): Massachusetts General Hospital, Boston, MA Children's Hospital, Boston, MA PROGRESS DURING THE CURRENT FUNDING PERIOD: This program has now completed its second year. During this period 17 publications have resulted from program related studies. A number of these have appeared in high impact journals and 11 list multiple authors who are part of this Program Project. Overall progress has been excellent. Project 1, "Structure and Function of New Blood Vessels," is directed by Dr. Harold Dvorak, in conjunction with Dr. Laura Benjamin. The studies under Specific Aim 1 where the investigators characterized new blood vessel induction by VEGF-A versus PIGF, VEGF-A/PIGF heterodynamers and FGF, are now completed and the work published in Nature Medicine. Specific Aim 2 is to employ inducible gene expression in mammary tumors to overexpress or not express the angiogenic factors studied under Specific Aim 1. These studies are underway and have resulted in two publications. Specific Aim 2 will use chip technology to profile genes that are differentially expressed in 'mother' vessels in response to local overexpression of VEGF-A or PIGF. Several novel genes have been characterized in the first two years of the project and many other potentially important genes also identified. Two manuscripts are in preparation describing this work. Project 2, Signaling Pathways that Determine Vascular Structure and Function, is the newly proposed project in this supplement and is considered in detail below. It is noted that Dr. Benjamin is a co-author of six of the 17 publications listed, several of which are very relevant to proposed supplement Project 2. Project 3, "Role of Placental Growth Factor in Normal and Neoplastic Skin Angiogenesis," is led by Dr. Michael Detmar. Specific Aim 1 is a study of the role of PIGF in skin vasculaturation and in experimental skin inflammation employing transgenic animal models. A novel transgenic mouse model for the targeted overexpression of human PIGF-2 in basal epidermal keratinocytes and other cells has been made. Studies of these animals have resulted in a paper published in Blood. Specific Aim 2 will employ these models to study chemically-induced skin cancer. Initial results suggest that PIGF plays a role in epithelial tumorigenesis. Specific Aim 3 will employ transfected PIGF and semaphorin D gene constructs to study the effects of modulating angiogenesis on the growth of human squamous cell carcinoma xenotransplants. Stably transfected cell lines have been obtained to pursue this aim and data are now being collected on these models. Project 4, "Inhibition of Angiogenesis by Thrombospondin-1," is led by Dr. Jack Lawler with the participation of Dr. R. Khosravi-far and Dr. S. Parangi. Specific Aim 1 seeks to characterize the CD36 receptor complex on endothelial cells to which TSP-1 binds. Specific Aim 2 will study mechanisms involved in TSP-1-induced apoptosis. Work is progressing on these aims, but appears quite preliminary. Dr. Lawler is co-author of three papers that report work on the ligand TSP-1 which have appeared in high impact journals. In addition, there are four cores (Administration, Morphology, Cell Biology, and Genomics) which are all operational and fulfill their role in the overall Program Project. Overall progress, as noted above, has been excellent.

DESCRIPTION (provided by applicant): This program project focuses on the structure and function of tumor blood vessels from many angles: roles and functions of angiogenic cytokines and endogenous inhibitors in tumors and in surrogate tumor blood vessels, the gene expression induced by these factors and their role in tumor angiogenesis, and the impact of angiogenic cytokines and angiogenesis on tumor progression.该提案概述了一系列实验，这些实验集中在主要血管生成细胞因子下游的主要信号通路之一，即AKT途径，作为许多肿瘤血管异常的介体：它们的大小较大，较差，渗透率增加和不稳定。我们的初步数据表明，生理血管生成中的AKT信号传导涉及非常精确的“ ON”和“ OFF AKT信号的开关”。但是，当抑制这种关闭开关时，所得的血管概括了肿瘤血管的许多方面，其他血管异常的血管和“母血管”，DVorak博士创造了一个术语，描述了由VEGF-A过度表达形成的血管，而VEGF-A和其他细胞因子则形成了血管。该赠款申请旨在探索AKT在“母血管”/“肿瘤血管”形成中的作用，以及下游AKT靶标对这些异常血管的个体特征和功能的影响。我们还建议探索TSP-1调节AKT信号传导的新颖发现背后的机制。该项目编写了3年，以使其能够折叠到该计划项目的现有资金时间表。目的：1。检验以下假设：Akt活性的上调足以概括异常的血管的结构和功能，让人联想到非肿瘤环境中肿瘤血管2。确定介导AKT的下游信号传导途径会影响AKT 3。探索3。 合作机构：马萨诸塞州马萨诸塞州马萨诸塞州马萨诸塞州 马萨诸塞州波士顿儿童医院 在当前资金期间的进展：该计划现在已经完成了第二年。在此期间，有17个出版物是由计划相关研究引起的。其中许多出现在高影响期刊中，11位列表了该计划项目的一部分的多个作者。 总体进步非常好。 Harold Dvorak博士与Laura Benjamin博士一起执导了项目1，“新血管的结构和功能”。 在特定目标1下的研究，研究人员通过VEGF-A与PIGF，VEGF-A/PIGF异差不清和FGF进行了新的血管诱导，现在已经完成，并且在自然医学上发表了工作。 具体目的2是在乳腺肿瘤中采用诱导基因表达来过表达或不表达在特定目标下研究的血管生成因子。这些研究正在进行中，并导致了两份出版物。 特定的目标2将使用芯片技术来介绍响应于VEGF-A或PIGF局部过表达的“母亲”血管中差异表达的基因。该项目的前两年已经表征了几种新型基因，并且也确定了许多其他潜在的重要基因。正在准备两个手稿来描述这项工作。 项目2，确定血管结构和功能的信号通路是该补充剂中新提出的项目，下面详细考虑。值得注意的是，本杰明博士是列出的17个出版物中六本的合着者，其中一些与拟议的补充项目2非常相关。 项目3，“胎盘生长因子在正常和肿瘤皮肤血管生成中的作用”，由迈克尔·德玛（Michael Detmar）博士领导。特定的目标1是对使用转基因动物模型的皮肤血管截然和实验性皮肤炎症中的作用研究。已经制造了一种新型的转基因小鼠模型，用于在基底表皮角质形成细胞和其他细胞中靶向人PIGF-2的靶向过表达。对这些动物的研究导致了一篇论文中发表的血液。具体目标2将采用这些模型研究化学诱导的皮肤癌。最初的结果表明，PIGF在上皮肿瘤发生中起作用。具体的目标3将采用转染的pigf和semaphorin d基因构建体来研究调节血管生成对人类鳞状细胞癌异种植物生长的影响。已经获得了稳定的转染细胞系来追求此目标，并且现在正在这些模型上收集数据。 项目4，“抑制血小板传播1的血管生成”，由杰克·劳勒（Jack Lawler）博士主持。特定目标1试图表征TSP-1结合的内皮细胞上CD36受体复合物。具体目标2将研究参与TSP-1诱导凋亡的机制。这些目标正在进展，但似乎很初步。 Lawler博士是三篇论文的共同作者，这些论文报告了在高影响期刊中出现的配体TSP-1的工作。 此外，还有四个核心（给药，形态学，细胞生物学和基因组学）都在运作并履行其在整个程序项目中的作用。如上所述，总体进步非常出色。