Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Regulatory Biology

Department

College of Sciences and Health Professions

First Advisor

Kondratov, Roman

Subject Headings

Biology

Abstract

INTRODUCTION The Naked Mole Rat [ Heterocephalus glaber] is a type of rodent -with the highest average lifespan-30 years-among all the rodent species. It lives underground in sealed burrow systems with little to no exposure to day-night transitions on the surface. It shows polyphasic round the clock activity within its subterranean burrow system. The activity and physiology of most animals are governed by the biological circadian clock. The biological circadian clock is a system that oscillates with a rough periodicity of 24 hours. Environmental zeitgebers regulate the entrainment of the circadian clock to the 24-hour day-night cycle and light is the most important zeitgeber. We checked the circadian clock in the naked mole rat for possible modifications due to its special habitat. The oscillating circadian clock regulates various aspects of physiology and metabolism. So, we also investigated aspects of metabolic and environmental sensing systems in the naked mole rat, to build up a comprehensive picture of possible altered circadian physiology in this remarkable species. CENTRAL HYPOTHESIS I hypothesized that the naked mole rat, living in a light-sequestered habitat-may have evolved circadian, metabolic and nutrient sensing systems that are similar to that of the mouse but oscillate with much better rhythmicity and these differences positively influence the long life-span of the naked mole rat. RESULTS We found that the circadian clock genes oscillate with a different phase within the liver of the naked mole rat from that in the mouse and the glucose metabolic pathway genes show a synchronized phasing in the naked mole rat. We uncovered sharp differences in activity in the mTOR complexes between the two species. The mTOR complex-1 had a lower activity within the naked mole rat compared to that in the mouse whereas the mTOR complex-2 had higher activity within the naked mole rat. To check the possible role of promoter differences in driving gene expression, we analyzed the clock-control element motifs in the putative promoters of the naked mole rat clock-genes and found them similar to those in the mouse. It is possible that novel modes of circadian resonance, glucose metabolism, and environmental sensing have evolved in this long-lived species.

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