Yuan-Ping Han Assistant Professor Surgery, Pathology Keck School of Medicine

Education:
BS 1982 Biochemistry - Sichuan University, Chengdu, China
PhD 1996 Biomedical Sciences - Mount Sinai School of Medicine, NYU

Postdoctoral Research Fellowship:
1996-1999 University of Southern California/Children's Hospital Los Angeles

Started at USC: 1999

Research Topics: Cell Cycle, Growth & Proliferation, Immunology, Protein Chemistry/Enzymology

Research Description

The extracellular matrix (ECM) is essential for cell survival, migration, proliferation, and phenotype determination. ECM provides a micro environment to support cell lodging and also actively signals the cells in response to environmental changes. Controlled degradation of ECM, mediated by matrix metalloproteinases (MMP), is critical for development, wound healing and cancer metastasis. The long term goal of this lab is to elucidate the molecular biology of inflammation mediated ECM degradation in the pathogenesis of inflammation induced diseases including wound healing, liver fibrosis, and cancer metastasis.

Three ongoing research projects in this laboratory are:

Trans-differentiation of hepatic stellate cells in liver fibrosis. In response to injuries, such as viral infection or toxin exposure, the hepatic stellate cells undergo a phenotypic trans-differentiation changing from the vitamin A storage lipocytes into myofibroblasts which produces fibrillar collagen and creates contraction. To dissect the molecular mechanism of liver fibrogenesis we recently established an in vitro model which simulates the normal quiescent and inflammatory states in the sinusoids. The goal of this project is to address how the basement ECM keeps the stellate cells in quiescence and how the collective effects of IL-1 and collagen promote the trans-differentiation of the stellate cells. Further, we want to address how MMP participates in the trans-differentiation of the stellate cells. A systematic approach by combination of in vitro 3D cultures of stellate cells, protein biochemistry and molecular biology as well as in vivo animal model of gain or loss of functions has been used to address these questions.

Mechanism of MMP-9 activation in degenerative diseases: MMP-9, a type-IV collagenase, has been implicated in many diseases such as tumor metastasis, wound healing, liver failure and arthritis. MMP-9 is tightly controlled at multiple levels. The nascent MMP-9 retains its latency by interaction between a specific cysteine in the pro-domain and the zinc in the catalytic domain. Activation by cleavage of the pro-domain is an irreversible process for activation of the zymogen. The converting enzyme for proMMP-9 remains elusive although the activation has been well documented in many diseases. Using a unique approach by organ culture of human skin and 3D culture of hepatic stellate cells we identified TNF-alpha and IL-1 respectively in promoting the activation of proMMP-9 by human skin and hepatic stellate cells. The goal of this project is to identify the proMMP-9 converting enzyme(s) (tentatively called proMMP-9 Activators). To approach the goal we have applied protein biochemistry, proteomic and genomics. We believe that identification of the proMMP-9 activator holds the promise to further understand the molecular basis of cancer metastasis, liver fibrosis and wound healing.

Acute phase factor mediated inhibition of MMP-9. In response to injury large amount of acute phase factors are produced by the liver and reached to the wound site. We founded that an acute phase factor, alpha-1-antichymotrypsin, effectively inhibits the proteolytic activation of proMMP-9 probably through targeting the converting enzyme. The goal of this project is to study the injury mediated regulation of alpha-ACT expression and the biochemical mechanism of its inhibition of the proMMP-9 activator. An integrated approach by combination of molecular biology and protein biochemistry and animal model has been applied.

Selected Publications

Yan C, Zhou L, Han YP. - Contribution of hepatic stellate cells and matrix metalloproteinase 9 in acute liver failure. - Liver Int [ 2008 ] May 26; . PubMed

Han YP, Yan C, Garner WL. - Proteolytic Activation of Matrix Metalloproteinase-9 in Skin Wound Healing Is Inhibited by alpha-1-Antichymotrypsin. - J Invest Dermatol [ 2008 ] Apr 10; . PubMed

Cheng CF, Fan J, Fedesco M, Guan S, Li Y, Bandyopadhyay B, Bright AM, Yerushalmi D, Liang M, Chen M, Han YP, Woodley DT, Li W. - Transforming growth factor alpha (TGFalpha)-stimulated secretion of HSP90alpha: using the receptor LRP-1/CD91 to promote human skin cell migration against a TGFbeta-rich environment during wound healing. - Mol Cell Biol [ 2008 ] May;28(10):3344-58 . PubMed

Goldberg MT, Han YP, Yan C, Shaw MC, Garner WL. - TNF-alpha suppresses alpha-smooth muscle actin expression in human dermal fibroblasts: an implication for abnormal wound healing. - J Invest Dermatol [ 2007 ] Nov;127(11):2645-55 . PubMed

Han YP, Yan C, Zhou L, Qin L, Tsukamoto H. - A matrix metalloproteinase-9 activation cascade by hepatic stellate cells in trans-differentiation in the three-dimensional extracellular matrix. - J Biol Chem [ 2007 ] Apr 27;282(17):12928-39 . PubMed

Han YP. - Matrix metalloproteinases, the pros and cons, in liver fibrosis. - J Gastroenterol Hepatol [ 2006 ] Oct;21 Suppl 3:S88-91 . PubMed

Han YP, Downey S, Garner WL. - Interleukin-1alpha-induced proteolytic activation of metalloproteinase-9 by human skin. - Surgery [ 2005 ] Nov;138(5):932-9 . PubMed

Han YP, Zhou L, Wang J, Xiong S, Garner WL, French SW, Tsukamoto H. - Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen. - J Biol Chem [ 2004 ] Feb 6;279(6):4820-8 . PubMed