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

• 批准号: 8403681
• 负责人: ALEKSANDER S. POPEL
• 金额: $ 53.44万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-13 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403681
• 关键词: Advanced Malignant Neoplasm; Angiogenesis Inhibitors; Angiogenesis Pathway; Animal Model; Bioinformatics; Biological; 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; Coupled; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Drug Design; Equilibrium; Extracellular Matrix; Fatty acid glycerol esters; Feedback; Female; Genetic Engineering; Goals; Growth; Growth Factor; Homeostasis; Human; Hypoxia; Hypoxia Inducible Factor; Image; Immune; Indiana; Knowledge; Laboratories; Ligands; Link; MCF7 cell; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Matrix Metalloproteinases; Measurement; Methodology; Methods; Mining; Modeling; Molecular; Molecular Models; Mus; Nature; Neoplasm Metastasis; Pathogenesis; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Play; Primary Neoplasm; Process; 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; Tissues; Translating; Translations; Tumor Angiogenesis; Tumor stage; United States; Universities; Validation; 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; computer studies; design; enhanced green fluorescent protein; human disease; hypoxia inducible factor 1; imaging modality; in vivo Cellular and Molecular Imaging Centers; inhibitor/antagonist; insight; malignant breast neoplasm; member; molecular imaging; molecular modeling; multi-scale modeling; neovascular; novel therapeutics; optical imaging; overexpression; pharmacokinetic model; receptor; red fluorescent protein; research study; response; scale up; simulation; tool; tumor; tumor microenvironment; tumor progression

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.

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来生长和转移。血管生成受多种刺激物和抑制物的调节，这些刺激物和抑制物在生理条件下维持血管稳态。这种血管生成平衡倾向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）起着重要作用。在内源性抗血管生成因子中，已经鉴定了几种完整蛋白质，例如血小板反应蛋白-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以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，有必要发展基于预测实验的肿瘤血管生成分子详细的多尺度计算模型。这项研究将集中在乳腺癌。该项目的长期目标是开发乳腺癌血管生成生理组的此类模型。计算的发展将紧密耦合到最先进的乳腺癌成像在分子，细胞，微血管和组织水平使用动物模型。侵袭性人乳腺癌细胞系MDA-MB-231和侵袭性较低的人乳腺癌细胞系MCF-7将用于在雌性重度联合免疫缺陷（SCID）小鼠的乳腺脂肪垫中产生原位异种移植物。测量将包括在肿瘤发展的不同阶段的受体和配体表达的表征和定位;生长肿瘤中缺氧和微血管的时空发展;以及肿瘤微血管的功能特征，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，而其他数据将作为验证的手段。这些模型将扩展到人类疾病。这项研究将有助于更好地了解肿瘤血管生物学的基本原理，并有助于设计新的治疗方法和定量解释临床数据。计算和实验研究的协同结合应该提供对疾病性质的重要见解。