Dongsheng Cai, MD, Ph.D. Assistant Professor Department of Physiology dcai@physiology.wisc.edu

Research Interests: Stress and Inflammation in Metabolic Homeostasis

Our research focuses on investigating the roles of intracellular stress and inflammation pathways for physiological regulation and pathological dysfunction of metabolic homeostasis, with the long-term mission of identifying molecular mechanisms and developing therapeutic avenues for metabolic diseases particularly obesity and diabetes.

An abundance of evidence has emerged demonstrating a close link between metabolism and immunity. The metabolic diseases such as obesity and diabetes are consistently associated with a state of chronic low-level inflammation, which can be triggered by intracellular metabolic stresses. We have previously identified nuclear transcription factor NF-kB and its upstream kinase IKKb as an important pro-inflammatory pathway in mediating protein catabolism in skeletal muscle (Figure A) and insulin resistance in liver (Figure B). This research prelude has opened an intriguing branch of studying gene-environment interactions in molecular metabolic physiology.

We now start to investigate intracellular stress and inflammatory pathways in central nervous system for metabolic regulatory abnormalities. First, we want to study the interactions of inflammatory signaling cascades with neuronal regulatory network and the resultant pathogenic contributions to the metabolic dysfunctions seen in obesity, anorexia, diabetes and the associated metabolic syndromes. Second, we are interested in identifying counter mechanisms through intrinsic anti-stress and anti-inflammatory reactions at molecular levels in central nervous system. In addition, we take steps from the mechanistic understandings to develop cell therapy targeting stem cells, with an ultimate aim to extinguish cellular inflammation and to improve metabolic functions in the diseases.

Another relevant interest in the laboratory is to study the association of the stress and inflammatory pathways with protein metabolism. Our background work has demonstrated a striking catabolic action of over-activated IKKb/NF-kB on muscle contractile protein. We are further defining the molecular programs from inflammatory activation that lead to imbalance between protein catabolic and anabolic metabolism in skeletal and heart muscles. In parallel, we attempt to investigate the catabolic impact of inflammatory pathways on metabolic functional proteins among hormonal signaling and enzymatic components during the development of metabolic disorders. This scope of research addresses not only the deadly syndromes including skeletal muscle cachexia and heart muscle decay, but also the systemic metabolic diseases such as obesity and diabetes that are pathogenically related to loss of functional proteins in metabolic tissues.

Figure A. Muscle wasting upon selective IKKb/NF-kB activation in skeletal muscle Gross view of leg muscle (left), cross-section of thigh muscle in H&E staining (middle), and muscle fiber size in quadriceps through immunostaining (right) in wildtype mice (top) and muscle-specific transgenic mice having IKKb/NF-kB activation (bottom).	Figure B. Hepatic NF-kB suppression improves high-fat-diet-induced insulin resistance reflected by decrease in islets hypertrophy. Pancreatic islets size in wildtype control (top) and liver-specific transgenic mice having NF-kB suppression (bottom) under normal diet (left) and high-fat-diet (right) condition.

Selected Publications: Articles on PubMed

• Cai D, Yuan M, Frantz JD, Melendez PA, Hansen L, Lee J, and Shoelson SE. (2005). Local and systemic insulin resistance resulting from hepatic activation of IKKb/NF-kB. Nature Med. 11:183-190. Abstract | PDF PMID 15685173
  
  
• Cai D, Frantz JD, Tawa NE, Melendez PA, Oh B, Lidov H, Hasselgren PO, Frontera WR, Lee J, Glass DJ, and Shoelson SE. (2004). IKKb/NF-kB activation causes severe muscle wasting in mice. Cell. 119:285-298. Abstract | PDF PMID 15479644
  
  
• Cai D, Dhe-Paganon S, Melendez PA, Lee J, and Shoelson SE. (2003). Two new substrates in insulin signaling: IRS5/DOK4 and IRS6/DOK5. J Biol Chem. 278:25323-25330. Abstract | PDF PMID 12730241
  
  
• Cai D, Su Q, Chen Y, and Luo M. (2000). Effect of thyroid hormone deficiency on developmental spatial expression of Goa gene in brain of neonatal rat by differential display PCR and in situ hybridization. Brain Res. 864:195-204. Abstract | PDF PMID 10802026

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