Biosignature and Vector Development Core

生物特征和载体开发核心

• 批准号: 7930504
• 负责人: Gregory M Lanza
• 金额: $ 30.99万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7930504
• 关键词: Acids; Address; Adhesives; Affinity; Algorithms; Alkaline Phosphatase; Amino Acid Sequence; Amino Acids; Animals; Antibodies; Antibody Formation; Apoptosis; Arts; B-Lymphocytes; Bacteria; Bacteriophages; Baculoviruses; Binding; Biochemical; Biochemical Pathway; Bioinformatics; Biological; Biological Process; Biotin; Blood Platelets; Buffers; CD31 Antigens; Cancer Center; Capsid Proteins; Carcinoma; Categories; Cell Adhesion Molecules; Cell Line; Cell Proliferation; Cell Separation; Cell Surface Proteins; Cell Surface Receptors; Cell membrane; Cell surface; Cells; Chemicals; Chemistry; Chimeric Proteins; Clinic; Code; Collection; Colon Carcinoma; Communities; Complementary DNA; Complex; Computing Methodologies; Consultations; Coupled; Culture Media; Cyclic Peptides; Cysteine; Data; Data Set; Data Sources; Databases; Deoxyribonucleases; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Dialysis procedure; Disulfides; E-Selectin; ENG gene; Endoglin; Endothelial Cells; Endothelium; Energy Supply; Ensure; Enzyme-Linked Immunosorbent Assay; Epitopes; Escherichia coli; Family member; Fee-for-Service Plans; Flow Cytometry; Fluorocarbons; Future; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genome; Glioblastoma; Glycine; Glycoproteins; Golgi Apparatus; Graph; Harvest; Histidine; Hour; Hybridomas; ITGA5 gene; ITGB3 gene; Image; Immune; Inclusion Bodies; Incubated; Individual; Infection; Inflammation; Integrin alpha5beta1; Integrin alphaVbeta3; Integrins; Intercalated Cell; Intercellular adhesion molecule 1; Interphase Cell; Intracellular Membranes; Ionic Strengths; Knowledge; Laboratories; Letters; Libraries; Ligand Binding; Ligands; Literature; Lung; Lysosomes; Magic; Magnetism; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mammalian Cell; Mechanics; Medical; Membrane; Membrane Proteins; Methods; Mining; Minor; Mitochondria; Molecular; Molecular Profiling; Monitor; Monoclonal Antibodies; Multiple Myeloma; Mus; Myelin Associated Glycoprotein; Myelin P0 Protein; N-terminal; Names; Nanotechnology; Natural Killer Cells; Neoplasm Metastasis; New York; Normal tissue morphology; Nuclear; Nuclear Envelope; Nuclear Protein; Nuclear Proteins; Oligonucleotides; Ontology; Optics; Ovarian; PECAM1 gene; Pancreatic ribonuclease; Pathway interactions; Patients; Pattern; Peptide Library; Peptide Phage Display Library; Peptide Synthesis; Peptides; Peripheral Nerves; Peroxidases; Phage Display; Play; Polystyrenes; Population Heterogeneity; Positioning Attribute; Post-Translational Protein Processing; Procedures; Process; Property; Protein Engineering; Proteins; Protocols documentation; PubMed; Publishing; Radiology Specialty; Rattus; Reaction; Reagent; Recombinant Antibody; Recombinant Proteins; Recombinants; Reporting; Research; Research Personnel; Rewards; Role; SELE gene; Saccharomyces cerevisiae; Sampling; Screening procedure; Sepharose; Serum; Services; Set protein; Signal Pathway; Site; Sodium Chloride; Solid; Somatostatin; Source; Specificity; Spleen; Splenocyte; Staining method; Stains; Streptavidin; Structure; Sulfonic Acids; Surface; Suspension substance; Suspensions; Sweden; System; TNF gene; Techniques; Technology; Temperature; Tetanus Helper Peptide; Text; Therapeutic; Time; Tissues; Tokyo; Tumor Cell Invasion; Tumor-Derived; Tweens; Universities; Variant; Vascular Endothelial Cell; Vascular Endothelium; Washington; Weight; Work; Writing; abstracting; angiogenesis; antibody conjugate; base; biosignature; cDNA Library; cancer type; career; cell growth; clinically relevant; collagenase; design; directed evolution; dispase; experience; fd Phage; flasks; imaging modality; imaging probe; in vivo; interest; knowledge base; local drug delivery; magnetic beads; malignant breast neoplasm; melanoma; member; molecular imaging; monocyte; mutant; myelination; nanoparticle; neovasculature; neutrophil; nitrophenylphosphate; novel; overexpression; peptide structure; prognostic; programs; protein aminoacid sequence; protein protein interaction; receptor; repository; research study; response; skills; sodium phosphate; text searching; tool; tumor; tumorigenesis; tumorigenic; vector

CORE C3: Biosiqnature and Vector Development Core Introduction Molecular imaging agents are extending the potential of noninvasive medical diagnosis from basic gross anatomical descriptions to complicated phenotypic characterizations based upon the recognition of unique cellsurface biochemical signatures. "Molecular imaging" is now a prominent feature of most clinically relevant imaging modalities, which affords the opportunity for targeted diagnostic studies but also for image-monitored site-specific therapeutic delivery, much like the "magic bullet" envisioned by Paul Erhlich 100 years ago. As we have demonstrated, integrin-targeted perfluorocarbon nanoparticles can combine molecular imaging with local drug delivery, i.e. rational targeted therapy, and provide prognostic information about the expected response to treatment1-4. Common to all tumors are the demands for oxygenation, nutritive energy supplies, and development of a vasculature. Cell-matrix interactions, fundamental to tumor invasion and metastasis, as well as angiogenesis, are closely associated with cell membrane adhesion molecules referred to as integrins. The integrins are heterodimeric, transmembrane glycoproteins resulting from the combination of 19 alpha and 8 beta subunits. In addition to their adhesive functions, integrins are involved in the transduction of information along classical signaling pathways and are presumed to influence cellular proliferation and apoptosis of cancer and activated endothelial cells. As described in several programs of this SCCNE, antagonists of alphavbeta3-integrin and a5b1 integrin maybe coupled to nanoparticle surfaces and utilized for high affinity, high-specificity targeting of the neovasculature. Indeed, the role of alphavbeta3-integrin is well documented in melanoma and breast cancer metastasis, but varies temporally within and across tumor types. Whereas, less aggressive tumors have low expression or only transient expression of anb3-integrin, alambdab1-integrin is more frequently expressed by low malignant potential tumors in addition to aggressive carcinomas, e.g., in ovarian cancers6. Endothelial proliferations of glioblastomas may be phenotypically characterized into three subtypes 6:1) solid-glomeruloid ICAM-1, alpha2beta1,alpha3beta1,alpha5beta1 negative; 2) channeled-branching ICAM-1 negative, and alpha2beta1,alpha3beta1,alpha5beta1 positive; or 3) channeled-telangiectatic ICAM-1 ,alpha2beta1,alpha3beta1,alpha5beta1 positive. The variable expression of these molecules probably reflect different steps in the maturation of endothelium and further illustrates the need to develop arrays of targeted agents to properly segment and treat the heterogeneous population of tumor neovasculature. For ligand-targeted therapies to work efficiently, patients must be administered the appropriate individualized agent (or mixture of agents). The Siteman Center for Nanotechnology Excellence will establish this core for the development and characterization of targeting ligands to be used with current and future nanotechnology platforms within the center and more broadly at other centers. The approach tripartite combines the state-of-the art technologies of: 1) peptide phage display, 2) recombinant antibody production, and 3) bioinformatics to address the unmet need for unique tumor binding ligands.

核心C3：Biosiqnature和载体开发核心 介绍 分子影像学试剂正在从基本的大体上扩展非侵入性医学诊断的潜力 从解剖学描述到复杂的表型表征， 生化特征“分子成像”现在是大多数临床相关的一个突出特征， 成像模式，这为有针对性的诊断研究提供了机会，也为图像监测提供了机会。 针对特定部位的治疗传递，很像100年前Paul Erhlich设想的“魔术子弹”。正如我们 已经证明，整合素靶向的全氟化碳纳米颗粒可以将联合收割机分子成像与局部 药物输送，即合理的靶向治疗，并提供有关预期反应的预后信息， 处理1 -4. 所有肿瘤的共同点是对氧合、营养能量供应和肿瘤生长的需求。 脉管系统细胞-基质相互作用是肿瘤侵袭和转移以及血管生成的基础， 与称为整联蛋白的细胞膜粘附分子密切相关。整合素是 由19个α和8个β亚基组合产生的异二聚体跨膜糖蛋白。在 除了它们的粘附功能外，整合素还参与沿着经典的 信号通路，并被认为影响细胞增殖和细胞凋亡的癌症和激活 内皮细胞如该SCCNE的几个项目所述，α v β 3-整联蛋白和α 5 β 1的拮抗剂 整联蛋白可以偶联到纳米颗粒表面，并用于高亲和力、高特异性靶向所述纳米颗粒。 新生血管事实上，α v β 3-整联蛋白在黑色素瘤和乳腺癌中的作用已被充分证实。 转移，但在肿瘤类型内和跨肿瘤类型时间上变化。然而，侵袭性较低的肿瘤 表达或仅瞬时表达anb 3-整联蛋白，alambdab 1-整联蛋白更频繁地表达低水平的 除了侵袭性癌之外，例如，卵巢癌6.内皮 胶质母细胞瘤的增殖可在表型上表征为三种亚型：1）实性肾小球样 ICAM-1、α 2 β 1、α 3 β 1、α 5 β 1阴性; 2）通道分支ICAM-1阴性，且α 2 β 1、α 3 β 1、α 5 β 1阳性;或3） 通道性毛细血管扩张ICAM-1，α 2 β 1、α 3 β 1、α 5 β 1阳性。这些分子的可变表达可能 反映了内皮细胞成熟的不同步骤，并进一步说明了开发内皮细胞阵列的必要性。 靶向药物以适当地分割和治疗肿瘤新生血管的异质群体。为 配体靶向治疗有效地工作，患者必须给予适当的个体化药物 (or试剂的混合物）。 该Siteman中心纳米技术卓越将建立这一核心的发展和 靶向配体的表征将用于当前和未来的纳米技术平台， 中心，更广泛地说，在其他中心。三方方法结合了最先进的技术 1）肽噬菌体展示，2）重组抗体生产，3）生物信息学，以解决未满足的 需要独特的肿瘤结合配体。