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）：鉴于通过研究已经进化出极端生物学以生存的动物来发现新生物学和药物发现的已被证明的潜力，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。缅甸蟒是一种罕见的进食者，在一天内进食相当于其体重的一餐后，其总体代谢率增加约40倍，血浆甘油三酯增加160倍。1，2这种极端的代谢需求激活了有效、快速和可逆的器官生长，包括生理性心脏肥大。1，我们发现，餐后心脏肥大伴随着心脏保护机制，激活基因表达的有益变化，尽管循环甘油三酯非常高，但可以防止心脏脂质积聚。相反，心脏增加了参与脂质处理、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，我们鉴定了3种脂肪酸（FA）（肉豆蔻酸[C14：0; 40 <$M]、棕榈酸[C16：0;100 <$M]和棕榈油酸[C16：1; 7.5 当对蟒蛇或小鼠给药时，可促进有益的心脏适应3，而没有病理性脂质信号传导的迹象。这似乎是独立的过氧化物酶体增殖物激活受体信号;这些和其他数据使我们相信，这条途径是新的。此外，我们发现，水甘油孔蛋白基因，水通道蛋白7（AQP 7），是最有力的激活基因在大鼠心肌细胞与这些FA处理，其表达上调，在心脏中的FA处理的小鼠。我们制作了心肌细胞特异性AQP 7缺失小鼠，发现它们对肾上腺素能刺激有夸张的病理反应。这些数据，结合AQP 7基因在运动和疾病中的双向反应，表明AQP 7可能介导了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方面。首先，我们将阐明蟒蛇所利用的心脏保护机制，并将其应用于哺乳动物。第二，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，我们将探讨预防和治疗的潜力，脂肪酸之前或之后的病理性心脏刺激，分别。我们将确定这些脂肪酸修饰疾病的机制。第三，我们将定义的机制，蟒蛇的心脏经历回归后，肥大的增长。这些实验的结果应该提出新的信号通路，可能导致心血管疾病的治疗。