Predictive experiment-based multiscale models of angiogenesis in breast cancer

基于预测实验的乳腺癌血管生成多尺度模型

基本信息

批准号：
7623361
负责人：
ALEKSANDER S. POPEL
金额：
$ 58.22万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-13 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7623361
关键词：
Abbreviations Advanced Malignant Neoplasm Angiogenesis Inhibitors Angiogenesis Pathway Animal Model Arts Basement membrane Bioinformatics Biological Biological Assay Biology Blood Vessels Blood Volume Blood capillaries Breast Cancer Cell Breast Cancer Model Cancer cell line Cell Communication Cells Characteristics Clinical Clinical Data Clinical Trials Communities Computer Simulation Contrast Media Coupled Data Development Diagnosis Diagnostic Neoplasm Staging Disease Drug Design Drug Kinetics Endothelial Cells Engineering Enzyme-Linked Immunosorbent Assay Epidermal Growth Factor Equation Equilibrium Estrogens Extracellular Matrix Fatty acid glycerol esters Feedback Female Fibroblast Growth Factor Generations Goals Green Fluorescent Proteins Growth Growth Factor Homeostasis Horseradish Peroxidase Human Hypoxia Hypoxia Inducible Factor Image Immune Indiana Knowledge Laboratories Laser Scanning Confocal Microscopy Laser Scanning Microscopy Libraries Ligands Link MCF7 cell Magnetic Resonance Magnetic Resonance Imaging Malignant Neoplasms Mammary Neoplasms Mammary gland Matrix Metalloproteinases Measurement Methodology Methods Mining Modeling Molecular Molecular Models Monoclonal Antibodies Mus Nature Neoplasm Metastasis Neoplasms in Vascular Tissue Neuropilins Nitric Oxide Synthase Oxygen measurement, partial pressure, arterial PC3 cell line PGF gene Pathogenesis Patients Peptides Pharmaceutical Preparations Pharmacologic Substance Physiological Placental Growth Factor Platelet-Derived Growth Factor Play Primary Neoplasm Process Procollagen-Proline Dioxygenase Progesterone Receptors Progression-Free Survivals Protein Fragment Proteins Proteolysis Proteome Publishing Reaction Research Response Elements Role Signal Transduction Simulate Systems Biology Testing Therapeutic Therapeutic procedure Thrombospondin 1 Tissue Inhibitor of Metalloproteinases Tissues Translating Translations Tumor Angiogenesis Tumor stage United States United States Food and Drug Administration Universities Validation Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Vascular Permeabilities Vascular blood supply Whole Organism Xenograft procedure abstracting angiogenesis antiangiogenesis therapy base cancer imaging cancer type capillary clinical application design enhanced green fluorescent protein human disease imaging modality in vivo in vivo Cellular and Molecular Imaging Centers inhibitor/antagonist insight magnetic resonance spectroscopic imaging malignant breast neoplasm member molecular imaging molecular modeling multi-scale modeling neovascular novel therapeutics optical imaging overexpression pharmacokinetic model public health relevance receptor red fluorescent protein research study response scale up second harmonic simulation tool tumor tumor progression virtual

项目摘要

DESCRIPTION (provided by applicant): Project Summary/Abstract Tumors are angiogenesis-dependent as they require blood supply to grow and metastasize. Angiogenesis is regulated by a multitude of stimulators and inhibitors that maintain vascular homeostasis under physiological conditions. This angiogenic balance is tipped in favor of proangiogenic factors in cancer. The proangiogenic factors include many growth factors among which vascular endothelial growth factor (VEGF) plays a prominent role. Among endogenous antiangiogenic factors several whole proteins, e.g. thrombospondin-1, as well as protein fragments have been identified; most of the known fragments reside in the extracellular matrix. A quantitative understanding of how these factors interact to result in a growing vasculature and how to control this growth is presently lacking. To achieve a better understanding of these processes, the development of predictive experiment-based molecular-detailed multiscale computational models of tumor angiogenesis is necessary. This research will focus on breast cancer. The long-term goal of this project is to develop such models of the breast cancer angiogenesis physiome. The computational developments will be tightly coupled to state of the art breast cancer imaging at the molecular, cellular, microvascular, and tissue levels using animal models. The invasive human breast cancer cell line MDA-MB-231 and the less invasive human breast cancer cell line MCF-7 will be used to generate orthotopic xenografts in the mammary fat pad in female severe combined immune deficient (SCID) mice. The measurements will include the characterization and localization of receptor and ligand expression at the different stages of tumor development; temporal and spatial development of hypoxia and microvasculature in growing tumor; and functional characteristics of the tumor microvasculature such as blood volume and vascular permeability, and the extracellular matrix. Part of these data will serve as input to the computational models whereas other data will serve as a means for their validation. The models will be extended to human disease. The research will contribute to a better fundamental understanding of the tumor vascular biology and to the design of novel therapeutics and quantitative interpretation of clinical data. The synergistic combination of computational and experimental studies should provide significant insights into the nature of the disease. PUBLIC HEALTH RELEVANCE: Narrative Breast cancer is the most commonly diagnosed female malignancy in the United States. Angiogenesis or neovascular growth plays a key role in breast cancer development, invasion and metastasis. Using synergistic combination of computational and experimental methods, the project will provide a better quantitative understanding of angiogenesis stimulation and inhibition, leading to translation of fundamental knowledge into novel therapeutics.

描述（由申请人提供）：项目摘要/摘要肿瘤是血管生成依赖性的，因为它们需要血液供应才能生长和转移。血管生成受到多种刺激剂和抑制剂的调节，这些刺激剂和抑制剂在生理条件下维持血管稳态。这种血管生成平衡有利于癌症中的促血管生成因子。促血管生成因子包括多种生长因子，其中血管内皮生长因子（VEGF）发挥着重要作用。在内源性抗血管生成因子中，有几种完整的蛋白质，例如已鉴定出血小板反应蛋白-1以及蛋白质片段；大多数已知片段存在于细胞外基质中。目前缺乏对这些因素如何相互作用导致脉管系统生长以及如何控制这种生长的定量理解。为了更好地理解这些过程，有必要开发基于预测实验的肿瘤血管生成的分子详细多尺度计算模型。这项研究将重点关注乳腺癌。该项目的长期目标是开发乳腺癌血管生成生理组的模型。计算发展将与使用动物模型在分子、细胞、微血管和组织水平上最先进的乳腺癌成像紧密结合。侵袭性人类乳腺癌细胞系 MDA-MB-231 和侵袭性较小的人类乳腺癌细胞系 MCF-7 将用于在雌性严重联合免疫缺陷 (SCID) 小鼠的乳腺脂肪垫中产生原位异种移植物。测量将包括肿瘤发展不同阶段受体和配体表达的表征和定位；肿瘤生长过程中缺氧和微血管的时空发展；肿瘤微血管的功能特征，例如血容量和血管通透性以及细胞外基质。这些数据的一部分将作为计算模型的输入，而其他数据将作为其验证的手段。该模型将扩展到人类疾病。该研究将有助于更好地了解肿瘤血管生物学，并有助于设计新疗法和临床数据的定量解释。计算和实验研究的协同结合应该为疾病的本质提供重要的见解。公共卫生相关性：叙述乳腺癌是美国最常诊断出的女性恶性肿瘤。血管生成或新血管生长在乳腺癌的发展、侵袭和转移中起着关键作用。利用计算和实验方法的协同组合，该项目将提供对血管生成刺激和抑制的更好的定量理解，从而将基础知识转化为新的疗法。