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Lei Yin

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Primary Appointment: Molec & Integrative Physiology
Primary PIBS Dept.: Molecular and Integrative Physiology
PubMed Name: Yin L.
Lab Website

  Circadian rhythm is a self-sustained 24 hour cycle which regulates many important biological activities (1). Recent findings indicate that a critical relationship exists between circadian rhythms and energy homeostasis (2,3). Disruption of circadian rhythm may contribute to the onset and development of obesity and diabetes (4,5). Therefore, it is crucial to understand the fundamental mechanisms that confer a circadian periodicity on physiological and pathological processes. My laboratory is interested in three areas related to circadian clock and its controlled output physiology. With regarding to understanding how the circadian clocks are generated and modulated, we primarily focus on the dynamic regulation of circadian rhythms by the ubiquitination-proteasome system. With regarding to how circadian clocks drive the metabolic rhythm within a fasting-feeding cycle, we mainly focus on the molecular basis underlying circadian-controlled glucose metabolism. With regarding to how disrupted circadian clock triggers onset and progression of insulin resistance and ultimately diabetes, we aim to create appropriate mouse models in order to address the causative role of impaired circadian clock in the onset and progression of metabolic diseases. The long-term goal in my laboratory is to understand the molecular pathways coupling circadian rhythm and metabolisms in order to design novel approaches in prevention and treatment of diabetes.

Major Research projects in my laboratory

Currently we are focusing on two major research projects in my laboratory. One is related to identify the specific E3 ligase as well as de-ubiquitin protease for each circadian clock protein. The other one is related to understand the metabolic function of circadian clock proteins in a tissue-specific manner. We use adenoviral-based gene transfer to over-express or knock down the clock proteins in liver or isolated primary hepatocytes and then examine the metabolic pathway affected.

Potential rotation projects
1. Studying how PPARalpha signaling regulates protein turnover of circadian protein in liver. Our preliminary data suggest altered clock protein expression in the liver of PPARalpha knockout mice. We hypothesize that PPARalpha regulates specific ubiquitin E3 ligase to target the protein turnover of clock protein. The project will characterize the biochemical basis of clock proteins ubiquitination and turnover rate upon manipulation of PPARalpha activity. The project will also identify the specific E3 ligase protein for the target clock proteins using both candidate approach and unbiased proteomic approaches. The project will also investigate the possible biological function of clock protein mutant (ubiquitination-deficient mutant) in the PPARalpha-mediated metabolic and anti-inflammation function.

2. Molecular mechanism for circadian dysfunction in obesity. Impaired circadian function has been found in both diet-induced obesity (via chronic high-fat diet feeding) and genetic obesity model (Ob/ob). Our own data suggest circadian dysfunction occurs in a tissue-specific and time-dependent manner. The rotation project will be firstly to characterize the clock mRNA and protein expression in the metabolic sensitive tissues harvested from HFD-treated mice. The project will then characterize the impact of the known signaling pathways that are associated with circadian clock in the HFD-treated mice. The project will then manipulate the candidate signaling molecules for their effects on on clock function using cell-based approaches.
In addition, we recently identified the clock protein as a cellular target of Resveratol, a natural compound found in the red wine, to regulate gluconeogenesis. We felt very exciting about this finding because this will establish a critical link between caloric restriction and circadian rhythm system. We will perform a detailed animal phenotyping and molecular analysis to understand this biological connection.