Regulation of Cellular Functions by Cyclic Nucleotide Phosphodiesterase 8

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和多重的调节作用。众所周知，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起作用。此外，在过去的几年里，已经清楚地表明，在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依赖过程。这种调节发生的最重要的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（PDEs）的不同同工酶。尽管已知超过100种不同的pde，但任何一种细胞类型通常表达不到6种pde，任何一种细胞室表达的pde甚至更少。我们目前的理解是，非常少量的pde将用于控制cAMP或cGMP的特定池。因此，不同的pde可以很容易地调节细胞中不同的过程。本研究的目标是在几种不同的细胞类型中确定哪些过程和蛋白质受PDE8A和PDE8B的调控。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）完全不敏感的不同寻常的特性，IBMX是所有同类PDE的高效小分子抑制剂。因此，pde8直到最近才被认为是细胞功能的主要调节因子。然而，我们小组最近的数据显示，它们对细胞功能的调节非常重要。我们的新数据显示，除了间质细胞外，PDE8s在肝细胞、棕色脂肪细胞和肾上腺束状细胞中也有高表达。由于我们现在已经有了PDE8A和PDE8B基因被破坏的小鼠，我们可以确定这两种PDEs对细胞功能的重要性，尽管目前还没有选择性的小分子抑制剂。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一种是由PDE家族调节的，以及它们是如何调节的。

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.