Insights from Ectothermic Vertebrates: Programming Cardiac Hypoxia Tolerance

变温脊椎动物的见解：编程心脏缺氧耐受性

• 批准号: BB/N005740/1
• 负责人: Gina Galli
• 金额: $ 44.87万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN005740%2F1
• 关键词: Insights; Ectothermic; Vertebrates; Programming; Cardiac

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".

一个人患心脏病的可能性随着年龄的增长而急剧增加，这是65岁以上人群死亡的主要原因。到2030年，大约20%的人口将达到65岁或以上，治疗心脏病的费用将增加两倍。迫切需要开发新的预防心脏病的治疗方法，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。许多心脏疾病是由于心脏供氧减少而发生的。缺氧，称为缺氧，会引发致命的心脏事件，如心脏病发作。最终，一个人从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。这在老年人中尤为重要；老年人不仅心脏缺氧的发病率较高，而且心脏的耐氧性也较差。目前的建议旨在制定一种策略，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一种被称为“发育规划”的自然生物过程来实现。发育规划是指在不改变婴儿基本基因蓝图的情况下，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。这些变化会持续到成年，甚至可以遗传给一个人的孩子和孙子。换句话说，一个人的生物学可以永久地受到其祖母成长环境的影响。这一惊人的发现为科学家们永久地“规划”个体生物学的各个方面打开了大门。事实上，目前正在开发的药物可以人为地修改基因，模拟发育程序的影响。这些所谓的“外源性药物”提供了一种方法来规划人类的心脏缺氧耐受性，保护他们免受心脏病的侵害。然而，在我们开发这些药物之前，我们需要知道需要修改哪些基因来产生耐缺氧的心脏。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：改变了一种非常古老的爬行动物物种——鳄龟的发育环境，使其能够耐受心脏缺氧。这是已知的唯一一种会发生这种情况的动物。虽然海龟的心脏结构与人类不同，但我们有许多共同的基因来调节心脏功能。因此，当前建议的直接目的是确定被调节为心脏缺氧耐受性程序的基因。我们的长期目标是利用这些信息来开发永久性地规划人类心脏缺氧耐受性的药物，提供终身保护以预防心脏病。这些目标与BBSRC的“整个生命过程中健康老龄化”战略优先事项密切相关。

项目成果

Draft Genome of the Common Snapping Turtle, Chelydra serpentina, a Model for Phenotypic Plasticity in Reptiles.

• DOI: 10.1534/g3.120.401440
• 发表时间: 2020-12-03
• 期刊: G3 (Bethesda, Md.)
• 作者: Das D;Singh SK;Bierstedt J;Erickson A;Galli GLJ;Crossley DA 2nd;Rhen T
• 通讯作者: Rhen T

Supplemental Results from Developmental plasticity of cardiac anoxia-tolerance in juvenile common snapping turtles (

幼年鳄龟心脏缺氧耐受性发育可塑性的补充结果（

• DOI: 10.6084/m9.figshare.8268677
• 发表时间: 2019
• 作者: Ruhr I

Supplemental Materials & Methods from Developmental plasticity of cardiac anoxia-tolerance in juvenile common snapping turtles (

补充材料

• DOI: 10.6084/m9.figshare.8268671
• 发表时间: 2019
• 作者: Ruhr I