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

磷酸二酯酶 8 协同作用：棕色脂肪和心脏功能的调节

• 批准号: 8914758
• 负责人: Joseph A Beavo
• 金额: $ 13.91万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8914758
• 关键词: Ablation; Address; Adipocytes; Adrenergic Agents; Adult; Affect; Angiotensins; Animals; Biological Process; Blood Circulation; Brown Fat; Calcium; Calcium Signaling; Cardiac; Cardiac Myocytes; Cell Line; Cell physiology; Cells; Communities; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic Nucleotides; Data; Development; Diet; Disease; Drug Targeting; Erectile dysfunction; Fatty acid glycerol esters; Future; Glucose; Goals; Grant; Guanine Nucleotide Exchange Factors; Heart; Heart Rate; Hepatocyte; Hypertrophy; Individual; Inflammation; Isoproterenol; Lipolysis; Malignant Neoplasms; Mediating; Metabolic Diseases; Minor; Mitochondria; Mitochondrial Matrix; Molecular; Mus; Nonesterified Fatty Acids; Obesity; Outer Mitochondrial Membrane; PDE4B; Pathology; Pathway interactions; Pharmaceutical Preparations; Phosphodiesterase Inhibitors; Physiological; Physiological Processes; Process; Production; Protein Kinase; Protons; Pulmonary Hypertension; Recruitment Activity; Regulation; Respiration; Role; Series; Signal Transduction; Steroid biosynthesis; Steroids; Testing; Therapeutic; Thermogenesis; Tissues; Triglycerides; Viagra; Work; adrenergic; cell type; design; glucose uptake; immortalized cell; in vivo; inhibitor/antagonist; leydig interstitial cell; phosphoric diester hydrolase; response; synergism

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.

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(PKA)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 调节的许多不同过程受到一系列环 AMP 降解磷酸二酯酶 (PDE) 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 PDE 一直是药理学上对抗多种病理的最受欢迎的方法。例如，药物伟哥(Viagra) 就是以这种方式发挥作用的。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，抑制单个 PDE 不足以调节该组织中的某些生理过程。例如，我们已经证明，经典的 PDE4 抑制剂在控制 Leydig 细胞中类固醇的产生方面完全无效，除非这些细胞的 PDE8 活性也受到抑制。这是协同作用过程的一个典型例子 - 几种通路调节剂一起作用比单独使用任何一种通路调节剂具有更大的效果。如果这个概念在多种组织中普遍有效，那么它将对未来 PDE 抑制剂的设计策略产生重大影响。因此，我们计划研究相同的原理是否适用于两个受 cAMP 高度调节并高度表达 cAMP 特异性 PDE8（如类固醇生成 Leydig 细胞）的不同组织。我们打算解决这个问题，是否需要抑制不止一种 PDE 才能有效调节这些组织中的 cAMP 依赖性过程。我们将研究多种 PDE 抑制剂治疗（包括新型 PDE8 抑制剂）对棕色脂肪组织 (BAT)/棕色脂肪细胞生热作用以及心肌细胞钙信号传导和心脏功能参数的影响。这些过程中的每一个都高度依赖 cAMP，并且每种细胞类型都表达高水平的 PDE8A。然而，据我们所知，它们中没有一个对它们的 cAMP 依赖性过程进行了单独的 PDE8 抑制的效果检查，特别是没有与这些细胞中表达的其他 PDE 的抑制结合起来。此外，我们将研究多种 PDE 在包括 Leydig 细胞和肝细胞在内的多种细胞类型中协同作用的分子机制，我们已经证明了 PDE 协同作用的发生。在过去 20 年里，许多制药公司花费了数十亿美元寻找选择性 PDE 抑制剂来治疗各种疾病，包括炎症、癌症和肥胖症。除了勃起功能障碍和肺动脉高压（由 cGMP 调节的过程）之外，这些努力仅取得了一定程度的成功。如果拟议的研究结果符合预期，它们将大大有助于解释为什么许多这些选择性抑制剂方法仅显示出较小的疗效。此外，这些数据可能会提出一种使用 PDE 抑制剂治疗各种疾病的替代方法，即使用针对多种 PDE 的药物。