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: 8676811
• 负责人: Joseph A Beavo
• 金额: $ 31.29万
• 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/8676811
• 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在许多不同的细胞类型的开发和功能中具有重要和多重调节作用。众所周知，CAMP在很大程度上通过激活cAMP依赖性蛋白激酶（PKA）和/或鸟嘌呤核苷酸交换蛋白EPAC发挥作用。重要的是，由CAMP/PKA/EPAC调节的许多不同过程受一系列环状AMP降解磷酸二酯酶（PDES）的高度控制。此外，通过选择性和特定抑制剂对单个环状核苷酸降解PDE的抑制一直是药理学在药理学上可以抵消多种病理的方法。例如，药物以这种方式起作用。但是，在最近的赠款期间，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CERTIN生理过程。例如，我们已经表明，经典的PDE4抑制剂在控制Leydig细胞中的类固醇产生方面完全无效，除非这些细胞的PDE8活性也受到抑制。这是协同过程的一个典型例子 - 几个途径调节器共同起作用比单独的途径更大。如果这个概念在几个组织中通常是有效的，那么将来对PDE抑制剂设计的策略具有很大的影响。因此，我们计划研究在两个不同的组织中相同的原理是否成立，这些组织高度高度调节并高度表达营地特异性PDE8，例如产生leydig细胞的类固醇。我们打算解决这个问题，需要抑制多个PDE，以有效调节这些组织中cAMP依赖的过程。我们将研究多种PDE抑制剂治疗的影响，包括新的PDE8抑制剂，对棕色脂肪组织（BAT）/棕色脂肪细胞的热发生以及心肌细胞和心脏功能参数的钙信号传导。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示高水平的PDE8A。但是，据我们所知，他们都没有对cAMP依赖性过程进行检查，仅对PDE8抑制作用的影响，尤其是与对这些细胞中表达的其他PDE的抑制相结合的效果。此外，我们将研究多种细胞类型中多种PDE的协同作用的分子机制，包括Leydig细胞和肝细胞，为此我们已经显示了PDE协同作用的发生。在过去的20年中，许多制药公司花费了数亿美元来寻找选择性PDE抑制剂，以治疗包括炎症，癌症和肥胖症在内的各种疾病。除了勃起功能障碍和肺动脉高压（由CGMP调节的过程）外，这些努力仅在略有成功。如果拟议的研究按预期进行的研究投票，他们将为解释为什么其中许多选择性抑制剂方法仅显示出较小的功效而做出重大贡献。此外，数据可能会提出一种通过使用靶向多个PDE的药物来治疗各种疾病的替代方法。