Insights from Ectothermic Vertebrates: Programming Cardiac Hypoxia Tolerance

一个人患心脏病的可能性随着年龄的增长而急剧增加，并且是65岁以上人群死亡的主要原因。到2030年，大约20%的人口将年龄在65岁或以上，治疗心脏病的费用将增加两倍。迫切需要开发预防心脏病的新疗法，以减少心脏病的福利和经济负担，并确保整个生命过程中的健康老龄化。许多心脏病的发生是由于心脏供氧减少。缺氧会引发致命的心脏事件，如心脏病发作。最终，一个人在心脏病发作中幸存下来的机会将取决于他们的心脏对缺氧的敏感性。这在老年人中尤其相关;不仅导致心脏缺氧的疾病的发生率较高，而且老年人的心脏对缺氧的耐受性也较低。目前的建议旨在制定一项战略，以永久提高个人对心脏缺氧的耐受性，提供终身保护，防止心脏病。这一目标将通过利用称为“发育规划”的自然生物过程来实现。发育编程是一个过程，通过这个过程，产前环境的变化可以永久地改变婴儿的基因，从而改变生物学，而不改变他们的基本遗传蓝图。这些变化持续到成年，甚至可以被一个人的孩子和孙子继承。换句话说，一个人的生物学可能会受到他们祖母成长环境的永久影响。这一惊人的发现为科学家们打开了一扇大门，使他们能够永久性地“编程”个人的生物学方面。事实上，目前正在开发的药物可以人工修改基因并模仿发育编程的效果。这些所谓的“毯子”提供了一种方法来编程人类的心脏缺氧耐受性，并保护他们免受心脏病的影响。然而，在我们开发这些药物之前，我们需要知道哪些基因需要修改以产生耐缺氧的心脏。在这方面，我的实验室最近有了一个令人兴奋和意想不到的发现：改变一种非常古老的爬行动物的发育环境，鳄龟，程序心脏缺氧耐受性。这是已知的唯一一种发生这种情况的动物。虽然海龟心脏的结构与人类不同，但我们有许多共同的基因来调节心脏功能。因此，本提案的直接目的是鉴定被调节以编程心脏缺氧耐受性的基因。我们的长期目标是利用这些信息开发出永久性编程人类心脏缺氧耐受性的毯子，提供终身保护，防止心脏病。这些目标与BBSRC的战略优先事项“终身健康老龄化”密切相关。

The likelihood of a person developing heart disease dramatically increases with age and represents the leading cause of death in people over 65. By 2030, approximately 20% of the population will be aged 65 or older and the cost for treating heart disease will triple. There is an urgent need to develop new treatments for the prevention of heart disease to reduce the welfare and economic burdens of cardiac disease and ensure healthy ageing across the life course. Many cardiac diseases occur as a result of a reduced oxygen supply to the heart. A lack of oxygen, termed hypoxia, triggers fatal cardiac events, such as heart attacks. Ultimately, the chance of a person surviving a heart attack will depend on the sensitivity of their heart to hypoxia. This is particularly relevant in the elderly; not only is there a higher incidence of diseases which cause cardiac hypoxia, but the elderly heart is also less hypoxia-tolerant. The present proposal aims to develop a strategy to permanently enhance an individual's tolerance to cardiac hypoxia, providing life-long protection against heart disease. This aim will be met by taking advantage of a natural biological process called "developmental programming". Developmental programming is the process by which changes in the prenatal environment can permanently modify a baby's genes, and therefore biology, without changing their basic genetic blueprint. These changes persist into adulthood, and can even be inherited by a person's children and grandchildren. In other words, an individual's biology can be permanently affected by the environment in which their grandmother developed. This astonishing discovery has opened the door for scientists to permanently "programme" aspects of an individual's biology. Indeed, drugs are currently being developed which can artificially modify genes and mimic the effects of developmental programming. These so-called "epidrugs" provide a means to programme cardiac hypoxia tolerance in humans and protect them from heart disease. However, before we can develop these drugs, we need to know which genes need be modified to produce a hypoxia-tolerant heart. In this regard, my laboratory has recently made an exciting and unexpected discovery: altering the developmental environment of a very ancient species of reptile, the snapping turtle, programmes cardiac hypoxia tolerance. This is the only known animal in which this occurs. Although the structure of the turtle heart is different to humans, we share many common genes that regulate heart function. Therefore, the immediate aim of the present proposal is to identify the genes which are modulated to programme cardiac hypoxia tolerance. Our long-term goal is to use this information to develop epidrugs which permanently programme hypoxia tolerance in the human heart, providing life-long protection against heart disease. These goals are strongly aligned to the BBSRC's Strategic Priority of "healthy ageing across the life-course".