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（由适用提供）：鉴于通过研究已经进化出极端生物学生存的动物来揭示新生物学和药物发现具有证明的潜力，我们最近将后源的缅甸蟒蛇作为动物模型，以发现有益心脏适应的新型途径。缅甸蟒蛇是很少的进料器，总体代谢率增加了约40倍，血浆甘油三酸血液的血浆甘油三酸酯在吃一顿饭的一天之内增加了160倍。这激活了基因表达的有益变化，尽管循环甘油三酸酯非常高，但仍可以防止心脏脂质积累。取而代之的是，心脏增加与脂质处理，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，我们确定了3种脂肪酸（FAS）的新型组合（myristic [C14：0; 40; 40; M] 在后python等离子体中，当对Python或小鼠施用时，酸）会促进有益的心脏适应3，而没有病理脂质信号传导的迹象。这似乎与PPAR信号无关。这些数据和其他数据使我们相信这一途径是新颖的。此外，我们发现水甘油酸蛋白基因Aquaporin 7（AQP7）是用这些FAS处理的大鼠心肌细胞中最有可能激活的基因，其表达在FA治疗的小鼠的心脏中进行了更新。我们已经制造了心肌细胞特异性AQP7无效小鼠，并发现它们对肾上腺刺激的病理反应夸大。这些数据与AQP7基因在运动和疾病中的双向反应结合，表明AQP7可能正在介导上述某些心脏保护机制。基于这些数据，该项目的目标是三倍。首先，我们将阐明Python使用的心脏保护机制，并将其转化为哺乳动物。其次，python后的许多方面 - 李氏心脏反应类似于有益的哺乳动物心脏反应对运动的反应。因此，我们将分别在病理心脏刺激之前或之后探索FAS的预防和治疗潜力。我们将定义这些FAS修改疾病能力的基础机制。第三，我们将定义Python心脏在肥厚性生长之后进行回归的机制。这些提出的实验的结果应表明可能导致心血管疾病治疗的新型信号通路。