Control of peptide hormone biosynthesis by PC2 and 7B2

PC2和7B2对肽激素生物合成的控制

基本信息

批准号：
7991571
负责人：
IRIS LINDBERG
金额：
$ 7万
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：
2009-12-03 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7991571
关键词：
Active Sites Adrenal Glands Affect Age Alanine Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Binding Binding Proteins Biochemical Biological Assay Blood Glucose Body Weight Brain Collaborations Complex Data Deposition Diabetes Mellitus Disease Endocrine Enzymes Exhibits Fatty acid glycerol esters Genes Glucagon Goals Grant Homeostasis Hypothalamic structure Insulin Knockout Mice Laboratory Finding Length Light Maps Measures Molecular Chaperones Mus Neurodegenerative Disorders Neurosecretory Systems Obesity Pancreas Parkinson Disease Pathology Peptides Phenotype Physiological Pituitary Gland Pituitary-dependent Cushing&apos s disease Polygenic Traits Prohormone Convertase Proprotein Convertase 2 Proteins Recombinants Regulation Role Serine Site Somatomedins Structure Testing Thinness Tissues Transgenic Mice Weight Work abeta accumulation food consumption human disease interest islet amyloid polypeptide knockout animal mouse model mutant novel overexpression peptide hormone peptide hormone biosynthesis phosphoneuroprotein 14 prevent protein aggregation protein expression public health relevance quantum relating to nervous system research study secretory protein synuclein trait

项目摘要

DESCRIPTION (provided by applicant): The maturation of peptide hormones within secretory tissues such as the pancreas, pituitary and adrenal requires the participation of specific proteolytic converting enzymes, the prohormone convertases, and small convertase binding proteins such as 7B2 and proSAAS. However, the universal expression of these proteins in all endocrine and neural tissues (including tissues which lack cognate convertases) indicates that these small neuroendocrine proteins may have roles unrelated to their actions on convertases. In previous cycles of this grant we have mapped the interaction sites of 7B2 with proPC2 and have detailed how 7B2 acts to prevent unfolding and aggregation of proPC2. We have used 7B2 knockout animals first to describe an unexpected Cushing's disease-like pathology, and most recently to identify a surprising new role for this protein in weight homeostasis. This role was recently independently substantiated by the Medrano laboratory finding that the 7B2 gene represents a quantum trait locus for leanness. In the current proposal we will investigate the structure of 7B2 both alone and in association with proPC2. We will explore interesting new preliminary data that 7B2 may act to block the aggregation and oligomerization of other secretory proteins, such as synuclein and amyloid-generating peptides. Together with Dr. Juan Medrano, we will investigate 7B2- overexpressing mouse models in order to define how 7B2 expression can affect polygenic traits such as obesity. We will compare the profile of hypothalamic peptides generated in a subcongenic line of mice which overexpresses 7B2 (B62D3), will investigate direct effects of 7B2 administration on blood glucose and body weight, and will generate a specific 7B2-overexpressing transgenic mouse which we expect will exhibit a lean phenotype. This work has important implications for diseases involving peptide hormone synthesis, such as diabetes, and is also relevant to the study of obesity. Lastly, our chaperone studies may be pertinent to neurodegenerative diseases involving protein aggregation, such as Alzheimer's and Parkinson's disease. PUBLIC HEALTH RELEVANCE: The synthesis of peptide hormones such as insulin and glucagon depends on the interaction of peptide-synthesizing convertases with small binding proteins within neuroendocrine tissues. Recent work has shown that these small binding proteins, 7B2 and proSAAS, may have other important physiological roles, such as chaperone activity and involvement in body weight homeostasis. In the present proposal, we plan to investigate these other roles.

描述（由申请人提供）：分泌组织（如胰腺、垂体和肾上腺）内肽激素的成熟需要特定蛋白水解酶、激素原转化酶和小转化酶结合蛋白（如 7B2 和 proSAAS）的参与。然而，这些蛋白质在所有内分泌和神经组织（包括缺乏同源转化酶的组织）中的普遍表达表明这些小神经内分泌蛋白可能具有与其对转化酶的作用无关的作用。在本次资助的前几个周期中，我们已经绘制了 7B2 与 proPC2 的相互作用位点，并详细说明了 7B2 如何发挥作用来防止 proPC2 的展开和聚集。我们首先使用 7B2 基因敲除动物来描述一种意想不到的库欣病样病理学，最近又发现了这种蛋白质在体重稳态中令人惊讶的新作用。 Medrano 实验室最近独立证实了这一作用，发现 7B2 基因代表了瘦身的量子性状基因座。在当前的提案中，我们将单独研究 7B2 的结构以及与 proPC2 结合的结构。我们将探索有趣的新初步数据，即 7B2 可能会阻止其他分泌蛋白（例如突触核蛋白和淀粉样蛋白生成肽）的聚集和寡聚化。我们将与 Juan Medrano 博士一起研究 7B2 过度表达的小鼠模型，以确定 7B2 表达如何影响肥胖等多基因性状。我们将比较过表达 7B2 (B62D3) 的亚同类系小鼠中产生的下丘脑肽的概况，将研究 7B2 给药对血糖和体重的直接影响，并将产生特定的 7B2 过表达转基因小鼠，我们预计该小鼠将表现出瘦弱的表型。这项工作对于涉及肽激素合成的疾病（例如糖尿病）具有重要意义，并且也与肥胖研究相关。最后，我们的伴侣研究可能与涉及蛋白质聚集的神经退行性疾病有关，例如阿尔茨海默病和帕金森病。公共健康相关性：胰岛素和胰高血糖素等肽激素的合成取决于肽合成转化酶与神经内分泌组织内小结合蛋白的相互作用。最近的研究表明，这些小结合蛋白 7B2 和 proSAAS 可能具有其他重要的生理作用，例如伴侣活性和参与体重稳态。在本提案中，我们计划研究这些其他角色。