Research

Research Interests:

  • Circadian rhythms in mammals
  • Biochemistry, genetics, molecular biology, functional genomics
  • Behavior, physiology, immunology

In mammals, circadian clocks regulate many aspects of 24-hr rhythms in behavior and physiology, and give organisms an adaptive advantage by preparing for transitions between day and night. In the natural world, the sun’s daily cycle dictates the measure of a day. However, our modern 24/7 life style impose external timing constrains that clash with our internal circadian physiology, often causing health problems (e.g., sleep disorders, accelerated aging, compromised mental performance, metabolic syndrome, cardiovascular diseases, and cancer). The major focus of my lab is to study the molecular, cellular and physiological mechanisms of circadian (~24) clocks in mammals. We ask i) how circadian oscillation is generated in a cell (cell autonomous) and in the central clock in the brain (within a neural network), and ii) how the molecular clock is integrated with cell and organ physiology.

We use cells and animals (mice and rats) as model systems and employ highly integrated approaches to study how the circadian clock keeps time. Circadian oscillation is a single cell phenomenon and the molecular mechanism is encoded in the genome. The clock ticks at multiple levels of circadian organization. Accordingly, we study the clock at the levels of cell, tissue, organ, and the organism. As opposed to traditional methods, we use kinetic (not just steady-state snapshots) and longitudinal methods (multiple days/cycles) to measure the temporal dynamics of molecular, cellular and physiological processes – an important, but largely under-appreciated aspect of biology. For instance, locomotor activity assay is used to study animal behavior and kinetic physiologic monitoring to study physiology. To examine gene expression, we use quantitative PCR, microarray and RNA seq to measure transcript levels. In particular, to study dynamics of gene expression, we engineer luminescent luciferase reporters and introduce them into cells and mice, and bioluminescence rhythms in cells and tissues can be monitored longitudinally through advanced real-time recording.

Leveraging our expertise and a battery of cell and animal clock models, my lab carries out the following main areas of research. i) To probe the biochemical and structural basis of cellular circadian behavior– a complex cellular behavior, and neural network basis of the central SCN clock. ii) To identify novel clock genes and modifiers and characterize how the genes and networks modulate clock function. Our overall strategy for this research is to use cellular clock models for gene discovery and mechanistic studies, and following discovery, gene and protein function will be studied at higher levels of circadian organization including animal behavior. iii) To investigate the extensive, bidirectional integration between the circadian clock and cell physiology, particularly the signaling pathways involved in innate immunity and cancer. While it is well accepted that the clock is anticipatory for time-of-day-dependent physiological needs, this research will uncover how the clock is responsive and adaptive to local physiology – a critically important aspect of proper timekeeping. Recently, we initiated a new line of research to iv) investigate the pathophysiological and neuroendocrine basis of circadian blood pressure regulation and asleep hypertension in the diurnal Nile grass rat model. Knowledge from this model is expected to provide mechanistic insights that would complement understanding from nocturnal animals such as mice.

Scientifically, our goal is to understand the molecular and cellular processes connecting clock genes to circadian physiology and behavior. Ultimately, we hope to gather sufficiently detailed knowledge to be able to effectively modulate our timekeeping system to improve treatments for clock-related disorders and enhance body fitness and health. Finally, I would like point out that physiology and behavior are systems problems, not simple outputs of single genes. In order to obtain integrative understanding, we must study a system using systems approaches: at both single gene/protein and genome-wide levels, and with not only spatial (within and between organs) but also temporal (day vs. night) resolution. As an advisor and mentor, I am acutely aware of the need for future biologists to obtain balanced training and to conduct independent research. I believe our research setup provides such an opportunity for training future generation scientists.