Fellowship for Lin: Effect of Testosterone on Regulation of Blood Pressure Circadian Rhythm Under Normal/light-dark Reversal in Male Mice

ABSTRACT Men are more prone to hypertension than women, especially below the age of 50. Testosterone plays a role in the development of cardiovascular disease (CVD). Longitudinal studies have showed testosterone levels decline with age in males. There is growing evidence that low testosterone levels incline toward CVD. In contrast, clinical studies showed testosterone supplement raised the mortality rate attributable to CVD. Thus, whether testosterone has beneficial or harmful cardiovascular effects remain controversial. Recently, it is appreciated that not only the level but also the normal circadian rhythm of blood pressure (BP) are essential. Disruption of BP circadian rhythm is emerging as an index for detrimental cardiovascular outcomes. Circadian rhythms are controlled by circadian clock that mainly synchronize in response to light signal by affecting the expression of clock genes. In mammals, Period 2 (Per2), a core clock gene, is an important regulator of circadian rhythms. Several studies have indicated the potential involvement of Per2 in regulation of the cardiovascular system. In modern society, an increasingly larger working population is involved in night-shift work or frequent travel across time zones that also causes circadian disruption, which is associated with increased CVDs. While multiple mechanisms may link the night-shift work with increased CVDs, I am interested in the potential contribution of desynchrony between the BP circadian rhythm and the light-dark cycle during the day- to night-shift transition. Altogether, I hypothesis that the clock gene Per2 mediates testosterone’s regulation of physiological BP circadian rhythm and the adjustment of BP circadian rhythm in response to time/light-shift. To explore the proposed hypothesis, wildtype, mPer2Luc (Per2 is fused with a luciferase reporter) and mPer2Brdm1 (Per2 knockout) male mice will be used in this project. In Aim 1, to determine whether clock gene Per2 mediates testosterone regulation of BP circadian rhythm. I will administer testosterone and examine BP circadian rhythm, clock gene mRNA, and Per2 protein oscillation in orchiectomized wildtype or Per2Luc mice. I will also use the Per2 knockout mice mPer2Brdm1 to determine whether Per2 mediates testosterone''s effect on BP circadian rhythm. In Aim 2, to determine the role of testosterone and Per2 in the adjustment of BP circadian rhythm in response to time/light-shift. As Aim1, I will determine the time course of adjustments in BP circadian rhythm, clock gene mRNA, and Per2 protein oscillation to the light-dark reversal by using orchiectomized wildtype, mPer2Luc and mPer2Brdm1 mice. Findings from this project will inform novel underlying mechanisms of testosterone on regulation of BP circadian rhythm and provide potential therapeutic targets in treating the patients who have cardiovascular diseases relevant to low testosterone or shiftwork.