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Identification of Novel Peptide Hormones

新型肽激素的鉴定

基本信息

批准号：
7708007
负责人：
IRIS LINDBERG
金额：
$ 22.5万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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：
2009-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7708007
关键词：
Address Adipocytes Bacteria Bioinformatics Biological Biological Assay Biological Testing Cells Chemicals Cleaved cell Code Collaborations Diabetes Mellitus Disease Drug Controls Enzymes Eukaryotic Cell Fatty acid glycerol esters Future Genome Glucose Hepatocyte Hormonal Hormones Human Genome In Vitro Individual Laboratories Lipids Liver Maryland Mediating Metabolic Metabolic Control Metabolism Muscle Muscle Cells Neurosecretory Systems Obesity Peptide Hydrolases Peptides Physiological Process Production Proprotein Convertases Proteins Reaction Recombinant Proteins Recombinants Screening procedure Signaling Molecule Site Testing Therapeutic Tissues Universities Work base blood glucose regulation design glucose metabolism lipid metabolism novel overexpression peptide hormone public health relevance research study reversed phase chromatography secretory protein sugar

项目摘要

DESCRIPTION (provided by applicant): One-fifth of the genome codes for secretory proteins; a small subset of these proteins represent peptide hormone signaling molecules. This proposal addresses the identification of novel secretory molecules involved in the control of metabolic function. Since the majority of neuroendocrine signaling molecules undergo proprotein convertase-mediated maturation, we plan to exploit the presence of genuinely cleavable sites in novel precursors to validate a set of potential peptide precursors. We will then test the bioactivity of correctly modified peptide products derived from these proteins. These assays will identify biologically active peptides acting on tissues that are key effectors of metabolic control: fat, liver and muscle. The proposed project represents a collaboration of the Lindberg laboratory with the secretory protein company Five Prime Therapeutics. Briefly, bioinformatics identification of large numbers of putative precursors by Five Prime will be followed by screening of HEK-expressed proteins with purified recombinant convertases (Lindberg laboratory). The information generated by the processing screen will then be used to direct large-scale recombinant protein production of promising precursors in the Lindberg laboratory. These purified precursors will be subjected to in vitro proteolytic and terminal maturation reactions in the Lindberg laboratory, and the resulting peptide products will then be tested in six metabolic assays targeted at fat, liver and muscle cell glucose metabolism at FivePrime Therapeutics. We expect that these studies will result in the identification of several novel peptide hormones contributing to metabolic control. These results should aid in our complete understanding of the hormonal control of glucose and lipid metabolism. PUBLIC HEALTH RELEVANCE: This is a discovery project which focuses on the identification of novel bioinformatics-identified peptide hormones. We will employ chemical processing of candidate precursors using physiological enzymes to make peptide mixtures which we will test in six different assays of glucose and lipid metabolism. We expect that these studies will result in the identification of several novel peptide hormones contributing to metabolic control.

描述（由申请人提供）：五分之一的基因组编码分泌蛋白；这些蛋白质的一小部分代表肽激素信号分子。该提案致力于鉴定参与代谢功能控制的新型分泌分子。由于大多数神经内分泌信号分子经历前蛋白转化酶介导的成熟，我们计划利用新型前体中真正可裂解位点的存在来验证一组潜在的肽前体。然后我们将测试从这些蛋白质衍生的正确修饰的肽产品的生物活性。这些测定将鉴定作用于代谢控制关键效应物组织的生物活性肽：脂肪、肝脏和肌肉。拟议的项目代表了 Lindberg 实验室与分泌蛋白公司 Five Prime Therapeutics 的合作。简而言之，通过 Five Prime 对大量推定前体进行生物信息学鉴定，然后用纯化的重组转化酶（Lindberg 实验室）筛选 HEK 表达的蛋白质。然后，处理筛选生成的信息将用于指导 Lindberg 实验室大规模重组蛋白生产有前途的前体。这些纯化的前体将在 Lindberg 实验室进行体外蛋白水解和终末成熟反应，所得肽产品随后将在 FivePrime Therapeutics 针对脂肪、肝脏和肌肉细胞葡萄糖代谢的六种代谢测定中进行测试。我们预计这些研究将鉴定出几种有助于代谢控制的新型肽激素。这些结果应该有助于我们完全了解葡萄糖和脂质代谢的激素控制。公共健康相关性：这是一个发现项目，重点是鉴定新型生物信息学鉴定的肽激素。我们将使用生理酶对候选前体进行化学处理来制备肽混合物，我们将在六种不同的葡萄糖和脂质代谢测定中对其进行测试。我们预计这些研究将鉴定出几种有助于代谢控制的新型肽激素。