Phosphodiesterase 8 Synergies: Regulation of Brown Fat, and Cardiac Functions

描述（由申请人提供）：众所周知，cAMP在许多不同细胞类型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（PKAs）和/或鸟嘌呤核苷酸交换蛋白Epac来发挥其作用。重要的是，cAMP/PKA/Epac调控的许多不同过程都受到一系列环AMP降解磷酸二酯酶（PDEs）的高度控制。此外，通过选择性和特异性抑制剂抑制单个环核苷酸降解PDEs已成为药理学上对抗许多病理的最受欢迎的方法。例如，药物伟哥(R)就是这样起作用的。然而，在最近的资助期间，我们发现至少在两种不同的组织中，单个PDE的抑制不足以调节该组织中的某些生理过程。例如，我们已经证明，一种经典的PDE4抑制剂在控制间质细胞的类固醇生成方面是完全无效的，除非这些细胞的PDE8活性也被抑制。这是协同作用过程的一个主要例子

DESCRIPTION (provided by applicant): It is well recognized that cAMP has important and multiple regulatory roles in the development and function of many different cell types. It is also known that cAMP exerts its effects largely through activation of cAMP- dependent protein kinases (PKAs) and/or the guanine nucleotide exchange protein, Epac. Importantly, the many different processes regulated by cAMP/PKA/Epac are highly controlled by a series of cyclic AMP- degrading phosphodiesterases (PDEs). Moreover, inhibition of individual cyclic nucleotide degrading PDEs by selective and specific inhibitors has been a favorite approach for pharmacologically counteracting a number of pathologies. For example, the drug Viagra(R) works in this manner. However, during the recent grant period we have made the discovery that in at least in two different tissues, inhibition of a single PDE is NOT sufficient to regulate certin physiological processes in that tissue. We have shown, for example, that a classic PDE4 inhibitor is completely ineffective in controlling steroid production in Leydig cells unless the PDE8 activity of these cells is also inhibited. This is a prime example of the process of synergy - several pathway modulators acting together to have a greater effect than either one alone. If this concept turns out to be generally valid in several tissues, it has GREAT implications for the strategies of PDE inhibitor design in the future. Therefore, we plan to investigate whether the same principle holds true in two different tissues that are highly regulated by cAMP and highly express the cAMP-specific PDE8 like steroid producing Leydig cells. We intend to address the question, does more than one PDE need to be inhibited in order to effectively regulate cAMP-dependent processes in these tissues. We will study the effects of multiple PDE inhibitor treatment, including a new PDE8 inhibitor, on thermogenesis in brown adipose tissue (BAT)/brown adipocytes, and on calcium signaling in cardiomyocytes and functional parameters of the heart. Each of these processes is highly cAMP-dependent and each cell type expresses high levels of PDE8A. However, none of them to our knowledge have had their cAMP-dependent processes examined for the effects of PDE8 inhibition alone and particularly not in conjunction with inhibition of other PDEs expressed in these cells. Moreover, we will investigate the molecular mechanisms underlying the synergistic action of multiple PDEs in a variety of cell types including Leydig cells and hepatocytes, for which we have already shown the occurrence of PDE synergies. Over the last 20 years, many drug companies have spent hundreds and hundreds of millions of dollars searching for selective PDE inhibitors to treat various disorders including inflammation, cancer, and obesity. With the exception of erectile dysfunction and pulmonary hypertension (processes regulated by cGMP) these efforts have been only marginally successful. If the proposed studies turnout as expected, they will contribute substantially to explaining why many of these selective inhibitor approaches have shown only minor efficacy. Moreover, the data will likely suggest an alternate approach for the treatment of various diseases with PDE inhibitors by using drugs that target more than one PDE.