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Stem cell, tumor and bone marrow microenvironment cross-talk in vivo

体内干细胞、肿瘤和骨髓微环境的串扰

基本信息

批准号：
7430502
负责人：
Dorothy A Sipkins
金额：
$ 230.25万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7430502
关键词：
Accounting Acylation Address Adhesives Affect Affinity Anatomy Animal Model Animals Antibodies Antigen-Presenting Cells Antigens Apoptosis Apoptotic Architecture Area Argon Arts Ascaridil Aspirate substance Avidin Award B-Lymphocytes Behavior Benign Bibliography Binding Biological Assay Biological Availability Biology Biotechnology Biotin Blood Blood Cells Blood Component Removal Blood Vessels Blood specimen Bone Marrow Bone Marrow Neoplasms Bone Marrow Stem Cell Bone Marrow Transplantation Bone marrow biopsy CD19 gene CD3 Antigens CD34 gene CSF3 gene CXCR4 Receptors CXCR4 gene Calcium-Sensing Receptors Calvaria Cancer Biology Cancerous Cell Adhesion Cell Adhesion Molecules Cell Communication Cell Line Cell Survival Cell Therapy Cell division Cell membrane Cell physiology Cell surface Cells Characteristics Charge Chemistry Chemokine, Other Chicago Class Clinical Clinical Research Coculture Techniques Collaborations Communication Communities Complex Confocal Microscopy Count Culture Media DNA Dana-Farber Cancer Institute Data Death Rate Dendritic Cells Dependence Depth Detection Development Dextrans Dimensions Discipline Disease Docking Dose Drug Delivery Systems Drug Monitoring Dyes E-Selectin Elements Encapsulated End Point Endothelial Cells Engineering Engraftment Environment Erythroid Cells Ethylene Glycols Event Exhibits Experimental Animal Model Experimental Models Exposure to Extracellular Matrix Extracellular Matrix Proteins Film Flow Cytometry Fluorescence Fluorescent Antibody Technique Fostering Future Galium Gases General Hospitals Goals Green Fluorescent Proteins Growth Growth Factor Half-Life Harvest Hematologic Neoplasms Hematology Hematopoiesis Hematopoietic Hematopoietic stem cells Heterogeneity Histology Home environment Homeostasis Homing Homologous Gene Hour Human Hybrids ITGAM gene ITGAX gene Image Image Analysis Imaging Techniques Immersion Investigative Technique Immune Immunocompromised Host Immunofluorescence Immunologic Immunohistochemistry Immunology Immunomagnetic Separation In Vitro Incubated Individual Inflammatory Injection of therapeutic agent Institution Integrin alpha4beta1 Integrin alpha5beta1 Interphase Cell Invasive Investigation Journals Knowledge Krypton Label Laboratories Laboratory Research Lasers Lateral Lead Learning Legal patent Letters Leukemic Cell Leukemic Hematopoietic Stem Cell Life Ligands Lipids Liposomes Literature Localized Location Longitudinal Studies Lymphoid Magnetic Resonance Imaging Magnetism Maintenance Malignant - descriptor Malignant Neoplasms Manuals Manufacturer Name Marrow Massachusetts Measures Mediating Mediator of activation protein Medical Medicine Membrane Membrane Fluidity Metastatic Neoplasm to the Bone Marrow Methods Microscope Microscopy Microspheres Minority Modeling Molecular Molecular Probes Molecular Profiling Molecular Target Molecular and Cellular Biology Mus Mutation Myelogenous N-Cadherin Nanotechnology Natural regeneration Nature Neoplasm Metastasis Neoplastic Endothelial Cell Neurons Normal Cell Numbers Occupations Oncology Organic solvent product Osteoblasts Outcome P-Selectin Pathologic Pathology Patients Pattern Perivascular Neoplasm Pharmaceutical Preparations Phosphorylcholine Photons Physical Chemistry Physics Physiological Play Polyethylene Glycols Polymer Chemistry Polymerase Chain Reaction Population Positioning Attribute Pre-B Acute Lymphoblastic Leukemia Probability Process Property Proto-Oncogene Protein c-kit Protocols documentation RNA Radiology Specialty Range Rate Reaction Receptor Cell Recording of previous events Regulation Research Research Design Research Ethics Committees Research Personnel Resistance Resolution Resources Reticular Cell Reverse Transcriptase Polymerase Chain Reaction Risk Role Running SCID Mice Saline Sampling Sapphire Scanning Science Scientist Screening procedure Sensitivity and Specificity Serum Shapes Signal Transduction Signal Transduction Pathway Site Small Interfering RNA Solutions Sorting - Cell Movement Speed Spleen Staging Standards of Weights and Measures Stem Cell Development Stem cell transplant Sterility Stimulus Stress Stromal Cell-Derived Factor 1 Stromal Cells Students Surface System T-Lymphocyte Tail Techniques Technology Testing Therapeutic Thinking Time Tissue Banks Tissues Titanium Titrations Training Translational Research Transplantation Treatment Protocols Tumor Angiogenesis Tumor Biology Tumor Cell Invasion Tumor Stem Cells Universities Vascular Cell Adhesion Molecule-1 Vascular Endothelial Cell Vascular Endothelial Growth Factors Veins Visible Radiation Water Week Work Xenograft Model Xenograft procedure abstracting angiogenesis antibody conjugate aqueous base body system bone cancer cell cancer stem cell cancer therapy career cell behavior cell growth cell motility cell type cellular imaging chemokine chemokine receptor chemotherapy clinical application clinically significant cranium cyanine cyanine dye cytokine cytotoxic day design desire detector dextran disorder control ethylene glycol experience fluorophore forging functional group human disease improved in vivo inhibitor/antagonist innovation insight interest intravital fluorescence microscopy intravital microscopy irradiation lens leukemia macrophage magnetic cell separation man microcalorimetry migration molecular dynamics molecular imaging mouse model nanoparticle neoplastic cell neovascularization new technology notch protein novel novel strategies novel therapeutics outcome forecast particle peripheral blood pre-clinical prevent progenitor programs prototype receptor research study response response to injury self-renewal size skills small molecule stem stem cells success targeted delivery therapeutic target tool trafficking tumor tumor eradication tumor growth two-photon uptake zeta potential

项目摘要

A growing body of evidence suggests that the host microenvironment plays an important role in the regulation of both normal and malignant stem cell self-renewal and differentiation. The specific locations, cellular components and molecular details of these stem cell niches are, however, little understood. Using in vivo confocal and multiphoton molecular imaging techniques to study cell interactions in the intact murine bone marrow (BM), we have defined a novel perivascular tumor and hematopoietic stem/progenitor cell (HSPC) niche. We have identified the molecules used by leukemic cells to access this niche, however the mechanisms governing HSC transit to these areas have not yet been defined. Moreover, the role of this niche in maintaining normal HSCs or coordinating specific HSC cell functions is unknown. Given the importance of HSC-based transplantation therapies as well as the clinical significance of tumor metastasis to the BM, there is great therapeutic potential in understanding these cellular interactions. The long-term goals of our research are, therefore, to define the molecular architecture and functional significance of this tumor and HSC niche using state-of-the-art in vivo imaging techniques combined with cell and molecular biology approaches. Specifically, we will 1) examine the mechanisms governing HSC transit and engraftment in these niches, 2) determine how tumor growth impacts the niche and whether tumor and benign HSCs compete within the niche, and 3) develop targeted nanoparticles to release encapsulated compounds in precise regions of the vascular niche. These nanoparticles will serve as a unique tool to elucidate the critical molecules that mediate HSC and tumor proliferation in the niche and as a prototype for a targeted drug delivery agent. Ultimately, we aim to use the knowledge from these studies to design specific anti-tumor treatments that spare normal hematopoiesis and to define factors that improve the efficacy of stem cell-based therapies.

越来越多的证据表明，宿主微环境在宿主免疫中起着重要作用。调节正常和恶性干细胞的自我更新和分化。具体地点，然而，这些干细胞小生境的细胞组分和分子细节知之甚少。使用in 活体共聚焦和多光子分子成像技术研究小鼠完整骨中细胞相互作用骨髓（BM），我们已经定义了一种新的血管周围肿瘤和造血干/祖细胞（HSPC）利基我们已经确定了白血病细胞进入这个小生境所使用的分子，然而，对这些地区的高铁过境管理尚未确定。此外，这一利基在维持正常HSC或协调特定HSC细胞功能是未知的。鉴于必须基于HSC的移植疗法以及肿瘤转移至BM的临床意义，有在理解这些细胞相互作用方面有很大的治疗潜力。我们研究的长期目标因此，确定这种肿瘤和HSC小生境的分子结构和功能意义使用最先进的体内成像技术结合细胞和分子生物学方法。具体而言，我们将1）研究HSC在这些小生境中的转运和植入机制，2）确定肿瘤生长如何影响小生境以及肿瘤和良性HSC是否在小生境内竞争，和3）开发靶向纳米颗粒以在血管的精确区域释放封装的化合物利基这些纳米颗粒将作为一种独特的工具来阐明介导HSC的关键分子，肿瘤在小生境中的增殖，并作为靶向药物递送剂的原型。最终，我们的目标是利用从这些研究中获得的知识可以设计出特定的抗肿瘤治疗方法，并确定提高干细胞治疗效果的因素。