Translating Python Biology to the Mammalian Heart

将Python生物学转化为哺乳动物心脏

• 批准号: 8704090
• 负责人: Leslie Anne Leinwand
• 金额: $ 40.7万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704090
• 关键词: Acids; Adrenergic Agents; Affect; Aftercare; American; Animal Model; Animals; Autophagocytosis; Biology; Blood; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Data; Disease; Eating; Exercise; Exhibits; Fatty Acids; Fatty acid glycerol esters; Free Radicals; Gene Expression; Genes; Goals; Growth; Heart; Heart Diseases; Heart Hypertrophy; In Vitro; Knockout Mice; Lead; Lipids; Mammals; Mediating; Metabolic; Mitochondria; Mus; Myocardial Infarction; Organ; Pathologic; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Physiological; Plasma; Preventive; Process; Pythons; Rattus; Role; Signal Pathway; Signal Transduction; Societies; Stimulus; Testing; Therapeutic; Translating; Triglycerides; adrenergic; base; drug discovery; economic cost; in vivo; multicatalytic endopeptidase complex; novel; prevent; public health relevance; research study; response; water channel

DESCRIPTION (provided by applicant): Given the proven potential for uncovering novel biology and for drug discovery by studying animals that have evolved extreme biology to survive, we have recently employed the post-prandial Burmese python as an animal model to discover novel pathways of beneficial cardiac adaptation. An infrequent feeder, the Burmese python exhibits a ~40-fold increase in overall metabolic rate and a 160-fold increase in plasma triglycerides within a day of eating a meal that can equal its body mass.1,2 This extreme metabolic demand activates potent, rapid and reversible organ growth, including physiologic cardiac hypertrophy.1,3 We found that post-prandial cardiac hypertrophy is accompanied by cardioprotective mechanisms that activate beneficial changes in gene expression and, despite very high circulating triglycerides, prevent cardiac lipid accumulation. Instead, the heart increases expression and activity of genes involved in lipid handling, mitochondrial oxidative capacity, and free radical scavenging.3 Importantly, we identified a novel combination of 3 fatty acids (FAs) (myristic [C14:0; 40 ¿ M], palmitic [C16:0;100 ¿M] and palmitoleic [C16:1; 7.5 ¿ M] acids) in post-prandial python plasma that when administered to either pythons or mice promotes beneficial cardiac adaptation3 with no signs of pathologic lipid signaling. This appears to be independent of PPAR signaling; these and other data lead us to believe that this pathway is novel. Moreover, we found that an aqua-glyceroporin gene, aquaporin 7 (AQP7), is the most potently activated gene in rat cardiac myocytes treated with these FAs and its expression is upregulated in hearts of FA-treated mice. We have made cardiac myocyte-specific AQP7 null mice and have found that they have an exaggerated pathological response to adrenergic stimulation. These data, in conjunction with bi-directional responses of the AQP7 gene in exercise and disease, suggest that AQP7 may be mediating some of the cardioprotective mechanisms described above. Based on these data, the goals of this project are three-fold. First, we will elucidate cardioprotective mechanisms utilized by the python and translate them to mammals. Second, many aspects of the python post- prandial cardiac responses resemble the beneficial mammalian cardiac response to exercise. Therefore, we will explore the preventive and therapeutic potential of the FAs before or after a pathologic cardiac stimulus, respectively. We will define the mechanisms underlying the ability of these FAs to modify disease. Third, we will define the mechanisms by which the python heart undergoes regression subsequent to hypertrophic growth. The results of these proposed experiments should suggest novel signaling pathways that may lead to therapeutics for cardiovascular disease.

描述（由申请人提供）：鉴于通过研究进化出极端生物学生存的动物来发现新生物学和药物发现的潜力已被证明，我们最近采用餐后缅甸蟒蛇作为动物模型来发现有益心脏适应的新途径。缅甸蟒蛇不常进食，在一天内吃完相当于其体重的一餐后，其总体代谢率会增加约 40 倍，血浆甘油三酯会增加 160 倍。1,2 这种极端的代谢需求会激活有效、快速和可逆的器官生长，包括生理性心脏肥大。1,3 我们发现，餐后心脏肥大伴随着心脏保护作用。 激活基因表达有益变化的机制，尽管循环甘油三酯非常高，但仍可防止心脏脂质积累。相反，心脏会增加参与脂质处理、线粒体氧化能力和自由基清除的基因的表达和活性。 3 重要的是，我们发现了 3 种脂肪酸 (FA) 的新组合（肉豆蔻酸 [C14:0; 40 ¿ M]、棕榈酸 [C16:0;100 ¿ M] 和棕榈油酸 [C16:1; 7.5] ¿ M]酸）存在于餐后蟒蛇血浆中，当给予蟒蛇或小鼠时，可促进有益的心脏适应3，且没有病理性脂质信号转导的迹象。这似乎与 PPAR 信号传导无关；这些和其他数据使我们相信这条途径是新颖的。此外，我们发现水甘油孔蛋白基因水通道蛋白 7 (AQP7) 是用这些 FA 处理的大鼠心肌细胞中最有效激活的基因，并且其表达在 FA 处理的小鼠心脏中上调。我们制作了心肌细胞特异性 AQP7 缺失小鼠，并发现它们对肾上腺素能刺激有过度的病理反应。这些数据与 AQP7 基因在运动和疾病中的双向反应相结合，表明 AQP7 可能介导上述的一些心脏保护机制。根据这些数据，该项目的目标有三个。首先，我们将阐明蟒蛇利用的心脏保护机制并将其转化为哺乳动物。其次，蟒蛇餐后心脏反应的许多方面类似于哺乳动物对运动的有益心脏反应。因此，我们将分别探讨 FA 在病理性心脏刺激之前或之后的预防和治疗潜力。我们将定义这些 FA 改变疾病能力的机制。第三，我们将定义蟒蛇心脏在肥大生长后经历退化的机制。这些拟议实验的结果应该表明可能导致心血管疾病治疗的新信号传导途径。