Research Area: Metabolic Adaptation in Health and Disease
1. Research Background
Metabolic pathways are dynamic networks that support tissue homeostasis and prompt changes in cell phenotype. The heart demands large amounts of substrate to regenerate ATP for contraction and to sustain biosynthetic reactions for replacement and maintenance of cellular materials. The Reznick lab utilises a non-standard organism, the naked mole–rat which has recently emerged as a rodent model of interest to biomedicine due to its extraordinarily long and healthy lifespan (>36 years). In previous work, we have shown that the naked mole-rat heart is intrinsically resistant to ischaemic damage by rewiring its metabolism. For example, naked mole-rats utilise an alternate substrate fructose instead of glucose to protect their tissues under hypoxic conditions. Furthermore, naked mole-rats display many neonatal-like features within their myocardium including immature mitochondrial morphology and myofilament composition. These atypical cardiac features serve as adaptations against the naked mole-rat’s extremely hypoxic and hypercapnic environment and at the same time contribute to the negligible decline in heart function with age. Counter-intuitively, features like fructose metabolism and a fetal-like myocardium which are protective in the naked mole-rat, have been linked to disease-like states in mice and humans. On the other hand, a fetal-like myocardium is conducive to myocardial regeneration.
2. Research questions addressed by the group:
Using the naked mole-rat, the aim of the Reznick lab is:
- to discern the contribution of different metabolic programs towards states of cardiac fitness, disease and regeneration, and
- to understand the regulation guiding metabolic plasticity to enable us to manipulate and reprogram metabolism to achieve beneficial outcomes such as protection against hypoxia and switching on a regenerative mode.
We do this via three objectives:
- We use “omics” technologies to examine the genetic, epigenetic and post-translational features underlying naked mole-rat rewired metabolism, hypoxia tolerance and myocardial fitness. We thus not only gain insights into protective metabolic pathways but also identify novel candidate genes contributing to cardiac fitness to test in mice.
- We have previously shown that the naked mole-rat can survive extended periods under extreme hypoxia without apparent damage, by switching its metabolism to utilise fructose. Use of fructose in ischaemic conditions could therefore prove beneficial in other mammals. We therefore aim assess whether enhancing fructose metabolism via transgenic mouse models is protective under ischaemic conditions.
- The transcriptional landscape of the naked mole-rat myocardium has preserved several neonatal-like features. Since neonatal mammalian heart has regenerative capacity, a quality that is quickly lost after birth, naked mole-rats may be the first adult mammalian model for heart regeneration. This project will measure regenerative capacity of the adult naked mole-rat heart and the mechanisms by which it may retain its proliferative competency
3. Possible project(s):
- Project: Molecular basis underpinning the rewired metabolism in the naked mole-rat heart
Using a combination of omics technologies, the aim of the project is to understand the regulation of metabolic plasticity in the naked mole-rat. We are particularly interested in the pathways that are:
- switched on under hypoxic conditions, and
- the regulation which allows the naked mole-rat to retain a neonatal-like transcriptional landscape in the heart.
We will employ a combination of omics technologies including ATACseq, PTMs on the proteome (eg. phosphorylome and acetylome) and metabolomics. These studies will also help to identify novel candidate genes and pathways acting to protect the naked mole-rat against hypoxia and ageing-related cellular insults which will be further tested in mice.
- Project: Enhancing fructose metabolism in mouse heart to overcome ischaemic damage
The discovery that naked mole-rats switch to fructose metabolism to support ATP production during an acute anoxic insult shows that naked mole-rat metabolism has evolved a neat metabolic trick which allows glycolytic flux to continue under hypoxia by circumventing feedback inhibition at the PFK1 enzyme. Recently, a connection between fructose use and hypoxia has been reported in other systems suggesting that up-regulation of fructose metabolism during hypoxia in the naked mole-rat is part of a wider biological phenomenon and implicates a therapeutic strategy. We will generate transgenic mice with enhanced ability to metabolise fructose and test them for whole body hypoxia tolerance and protection against acute ischaemic episodes such as myocardial infraction.
- Project: Naked mole-rat as first adult mammalian model for myocardial regeneration.
The inability of the adult mammalian heart to regenerate after ischaemic injury is a major cause of heart failure in humans. In contrast, some vertebrate species like zebrafish and neonatal mice are capable of regeneration following myocardial injury through cardiomyocyte proliferation. The upstream triggers regulate the regenerative capacity are thought to be oxidative metabolism as the abrupt end to the proliferative window coincide with decreased anaerobic glycolytic capacity and a concomitant increase in mitochondrial function. Given the link between oxidative metabolism, metabolic reprogramming and regeneration, it is plausible that the naked mole-rat heart, which has retained a neonatal-like cardiac metabolism, harbours regenerative potential offering a much-needed adult mammalian model for cardiac regeneration to the field. We will examine whether the naked mole-rat heart harbours regenerative capacity and how the naked mole-rat deals with myocardial injury. Molecular mechanisms supporting regeneration or coping with myocardial injury will be investigated and further tested in mice.
4. Applied Methods and model organisms:
We use a non-standard animal model the naked mole-rat and transgenic mouse models to explore metabolic adaptations to severe hypoxic and ischaemic events with a focus on the cardiovascular system. An interdisciplinary approach comprised of in vivo physiology, molecular and biochemistry techniques as well omics technologies are used to assess metabolic adaptations and their contribution to the cardiovascular system in diseased and hypoxic states.
5. Desirable skills and qualifications:
We are looking for a motivated PhD student with a good working knowledge of biochemistry and molecular biology. A focus in cardiac function or omics methods and bioinformatics is an advantage.
- Park TJ,* Reznick J*, Peterson BL, et al. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science. 2017;356(6335):307-311. doi:10.1126/science.aab3896.