Regulation of Cellular Functions by Cyclic Nucleotide Phosphodiesterase 8

环核苷酸磷酸二酯酶 8 对细胞功能的调节

基本信息

批准号：
8072053
负责人：
Joseph A Beavo
金额：
$ 29.05万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8072053
关键词：
Ablation Acute Adipocytes Adipose tissue Adrenal Cortex Adrenal Cortex Hormones Adrenal Glands Affect Aldosterone Animals Brown Fat Cell physiology Cells Cholesterol Homeostasis Chronic Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cyclic Nucleotides Data Development Drug Delivery Systems Enzymes Family Fatty acid glycerol esters Functional disorder Genes Goals Guanine Nucleotide Exchange Factors Hepatocyte Hormones Individual Isoenzymes Lipids Lipolysis Liver Measurement Measures Mediating Methods Molecular Mus Pathway interactions Phosphodiesterase Inhibitors Phosphorylation Physiological Play Positioning Attribute Process Production Property Protein Kinase Proteins Regulation Role Steroids Testing Thermogenesis Time Tissues Viagra Work Zona Fasciculata base cell type expectation hormone regulation inhibitor/antagonist leydig interstitial cell phosphoric diester hydrolase polypeptide public health relevance response small molecule

项目摘要

DESCRIPTION (provided by applicant): It is well recognized that cAMP has important and multiple regulatory roles in the development and function of many different cells. It is also known that cAMP, works largely through activation of cAMP-dependent protein kinases and/or the guanine nucleotide exchange protein, Epac. Moreover, in the last few years it has become clear that specific compartments are present in most cells that serve to organize and regulate specific cAMP-dependent processes in the cells. One of the most important mechanisms by which this regulation occurs is through selective activation or inhibition of distinct isozymes of cyclic nucleotide phosphodiesterases (PDEs) in the cell. Although over 100 different PDEs are known, any single cell type usually expresses less than half a dozen of them and any single compartment even fewer. Our current understanding is that a very small number of PDEs will serve to control a particular pool of cAMP or cGMP. Therefore, different PDEs can easily regulate different processes in the cell. It is the goal of the proposed studies to identify in several different cell types which processes and proteins in that cell are regulated by PDE8A and PDE8B. The PDE8 family is a relatively newly discovered PDE family that is specific for cAMP and has the unusual property of being completely insensitive to isobutylmethylxanthine (IBMX), a highly effective small molecule inhibitor of all other PDEs of this class. As a result PDE8s have until recently not been implicated as major regulators of cellular function. However, recent data from our group now show that they can be very important to regulation of cell function. Our new data shows that in addition to Leydig cells, PDE8s are highly expressed in liver hepatocytes, brown fat cells, and adrenal fasciculata cells. Since we now have available mice having the PDE8A and PDE8B genes disrupted, we are in position to determine the importance of these two PDEs to cellular function, despite the fact that selective small molecule inhibitors are not yet available. Therefore, we propose to determine which of the several functions known to be modulated by cAMP in each of these cell types are regulated by this PDE family and how they do so. PUBLIC HEALTH RELEVANCE: The proposed studies will explore the role of a newly discovered and previously unstudied family of cyclic nucleotide phosphodiesterases, the PDE8s on adrenal, liver, and brown fat function. Preliminary evidence suggests that these PDEs are major regulators of cAMP controlled functions in these cell types. It is expected that the proposed studies will tell us which processes are regulated and how the regulation occurs at the molecular level. Just as another specific form of PDE is the target of the drug Viagra, so also it is quite possible that PDE8s may become the targets of drugs useful for treating adrenal, liver and adipose tissue dysfunction once we understand how they function in each of these tissues.

描述（由申请人提供）：众所周知，cAMP 在许多不同细胞的发育和功能中具有重要且多重的调节作用。还已知 cAMP 主要通过激活 cAMP 依赖性蛋白激酶和/或鸟嘌呤核苷酸交换蛋白 Epac 发挥作用。此外，在过去几年中，人们已经清楚大多数细胞中存在特定的区室，这些区室用于组织和调节细胞中特定的 cAMP 依赖性过程。这种调节发生的最重要机制之一是通过选择性激活或抑制细胞中环核苷酸磷酸二酯酶（PDE）的不同同工酶。尽管已知有超过 100 种不同的 PDE，但任何单一细胞类型通常表达的 PDE 不到六种，任何单个区室的表达量甚至更少。我们目前的理解是，极少数 PDE 将用于控制特定的 cAMP 或 cGMP 池。因此，不同的偏微分方程可以轻松调节细胞内的不同过程。拟议研究的目标是确定几种不同细胞类型中哪些过程和蛋白质受 PDE8A 和 PDE8B 调节。 PDE8 家族是一个相对较新发现的 PDE 家族，它对 cAMP 具有特异性，并且具有对异丁基甲基黄嘌呤 (IBMX) 完全不敏感的不寻常特性，IBMX 是此类所有其他 PDE 的高效小分子抑制剂。因此，直到最近 PDE8 才被认为是细胞功能的主要调节因子。然而，我们小组的最新数据表明它们对于细胞功能的调节非常重要。我们的新数据显示，除了 Leydig 细胞外，PDE8 在肝细胞、棕色脂肪细胞和肾上腺束状细胞中也高表达。由于我们现在拥有 PDE8A 和 PDE8B 基因被破坏的小鼠，因此我们能够确定这两种 PDE 对细胞功能的重要性，尽管选择性小分子抑制剂尚未可用。因此，我们建议确定这些细胞类型中已知由 cAMP 调节的几种功能中的哪些是由该 PDE 家族调节的以及它们是如何调节的。公共健康相关性：拟议的研究将探讨新发现且之前未经研究的环核苷酸磷酸二酯酶家族（PDE8）对肾上腺、肝脏和棕色脂肪功能的作用。初步证据表明，这些 PDE 是这些细胞类型中 cAMP 控制功能的主要调节因子。预计拟议的研究将告诉我们哪些过程受到调节以及调节如何在分子水平上发生。正如另一种特定形式的 PDE 是伟哥药物的靶点一样，一旦我们了解了 PDE8 在这些组织中的功能，它们也很可能成为用于治疗肾上腺、肝脏和脂肪组织功能障碍的药物的靶点。