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Characterization of Erbb Receptors in Nanoparticles

纳米颗粒中 Erbb 受体的表征

基本信息

批准号：
8859958
负责人：
Matthew Adrian Coleman
金额：
$ 31.85万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-07 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8859958
关键词：
Accounting Address Affinity Apolipoproteins Binding Binding Proteins Biochemical Biological Assay Biological Models Biotechnology Brain Brain Neoplasms Breast Cancer Patient Cell membrane Cells Complex Development Dimerization Disease Drug Targeting Environment Epidermal Growth Factor Epithelial ErbB4 gene Event Extracellular Domain Family G-Protein-Coupled Receptors Goals Growth Factor Heterodimerization Homo Homodimerization Human Lead Length Libraries Ligand Binding Ligand Binding Domain Ligands Lipid Bilayers Maintenance Malignant Neoplasms Mammary Neoplasms Mediating Membrane Membrane Proteins Methods Molecular Models Nanotechnology Organ Particle Size Peptides Phage Display Pharmaceutical Preparations Phospholipids Phosphotransferases Play Population Property Protein Binding Protein Denaturation Proteins Receptor Activation Receptor Protein-Tyrosine Kinases Resistance development Roche brand of trastuzumab Roentgen Rays Signal Transduction Solubility Solutions Structure Technology Therapeutic Therapeutic Agents Therapeutic Intervention Time Tissues Trastuzumab Tyrosine Kinase Inhibitor Water X-Ray Crystallography apolipoprotein Lp(a+)aqueous carcinogenesis design extracellular humanized antibody imaging agent improved inhibitor/antagonist insight lapatinib malignant breast neoplasm member membrane model molecular modeling monomer nanoparticle new technology novel novel strategies novel therapeutics outcome forecast overexpression particle protein expression receptor reconstitution screening small molecule small molecule libraries tumor water solubility

项目摘要

DESCRIPTION (provided by applicant): Over 30% of proteins are bound to cell membranes, which makes them difficult to isolate in a soluble and active form. We propose to implement recently developed nanolipoprotein particles (NLPs) to allow the separation of membrane-bound proteins in an active form. NLPs are discoidal nanoparticles formed when an apolipoprotein and a population of phospholipids self-assemble into a lipid bilayer in an aqueous environment that can solubilize active membrane-bound proteins. In particular, we will focus on characterization of tyrosine kinase receptors, which mediate the spread of many cancers and are targets of several chemotherapeutics. The ability to study these receptors outside the cell environment will enable structural and mechanistic studies for improved understanding of carcinogenesis and other diseases. Given that membrane-associated proteins account for the majority of drug targets, it is important to develop novel technologies to gain access to this important class of proteins. This main goal is to develop generally applicable methods to produce, isolate and characterize the human type I tyrosine kinase receptors ErbB1, ErbB2, ErbB3 and ErbB4. The epidermal growth factor families of receptors are known to be important in cell signaling and carcinogenesis. These proteins are challenging to study because of their insolubility and tendency to aggregate in aqueous solutions. This proposal is focused on developing a new biotechnology application leading to formation of NLPs capable of solubilizing these and other membrane-bound proteins. The NLPs present a distinct advantage over currently used model membranes in terms of particle size monodispersity and solubility. This proposal will be carried out by synthesizing homo- and heterodimers of ErbB receptors in NLPs, characterizing them for structure and function and performing library screening in order to identify novel high-affinity peptides and small molecules that can serve as lead compounds for further development as drugs.

描述（由申请人提供）：超过30%的蛋白质与细胞膜结合，这使得它们难以以可溶性和活性形式分离。我们建议实施最近开发的纳米脂蛋白颗粒（NLP），以允许以活性形式分离膜结合蛋白。NLP是当载脂蛋白和磷脂群体在可溶解活性膜结合蛋白的水性环境中自组装成脂质双层时形成的盘状纳米颗粒。特别是，我们将集中在酪氨酸激酶受体，介导许多癌症的传播和几个化疗药物的目标的表征。在细胞环境外研究这些受体的能力将使结构和机制研究能够更好地理解致癌作用和其他疾病。鉴于膜相关蛋白占药物靶点的大多数，因此开发新技术以获得这类重要的蛋白质是很重要的。本研究的主要目的是开发普遍适用的方法来生产、分离和表征人I型酪氨酸激酶受体ErbB1、ErbB2、ErbB3和ErbB4。已知表皮生长因子受体家族在细胞信号传导和癌发生中是重要的。这些蛋白质是具有挑战性的研究，因为它们的不溶性和倾向于聚集在水溶液中。该提案的重点是开发一种新的生物技术应用，从而形成能够溶解这些和其他膜结合蛋白的NLP。NLP在粒径单分散性和溶解度方面比目前使用的模型膜具有明显的优势。该提案将通过在NLP中合成ErbB受体的同源和异源二聚体，表征其结构和功能并进行文库筛选来进行，以鉴定可作为先导化合物进一步开发为药物的新型高亲和力肽和小分子。