X. Long Zheng, M.D, Ph.D

Description of Research Expertise

RESEARCH SUMMARY:

Structure-function analysis and cofactor-dependent regulation of A Disintegrin And Metalloprotease with ThromboSpondin Type 1 repeats (ADAMTS) family, members 13 and 7.

RESEARCH DESCRIPTION:

ADAMTS13, a plasma metalloprotease, cleaves von Willebrand factor (vWF) and regulates vWF multimer sizes. Deficiency of ADAMTS13 activity leads to thrombotic thrombocytopenic purpura (TTP) and many other arterial thrombotic disorders. My colleague and I are interested in understanding of the pathogenesis of TTP by investigating the structural components of ADAMTS13 protease required for substrate recognition in vitro and in vivo. We are also interested in determining the epitopes anti-ADAMTS13 IgG autoantibodies bind. Finally, we are interested in identifying novel protein or non-protein cofactors that accelerate ADAMTS13 enzymatic function and in developing viral vector and cell-based molecular therapies for treatment of TTP and related disorders.

ADAMTS7, a closely related metalloprotease to ADAMTS13, cleaves cartilage oligomeric matrix protein (COMP). It has recently been identified as a risk factor for atherosclerosis and cardiovascular diseases. Little is known about the biochemistry and physiological functions of ADAMTS7 in atherosclerosis and thrombosis. My colleague and I are interested in understanding of the structure-function relationship of ADAMTS7 in recognition of novel substrates. In addition, we are interested in developing novel fluorescein-labeled peptide assays for assessing plasma ADAMTS7 activity in patients with various cardiovascular diseases.
Recombinant DNA and protein engineering, protein expression and purification, cell culture, light/fluorescent microscopy, confocal and electron microscopy, various other biochemical and biophysical assays, and murine models will all be employed in the laboratory.

The advances in these areas will not only shed more light on the pathogenesis of TTP and atherosclerosis, but also provide tools for diagnosis and treatment of TTP and many other arterial thrombotic disorders including myocardial infarction and ischemic stroke.

ROTATION PROJECTS:

1. Structural components of ADAMTS13 and ADAMTS7 required for cleavage of von Willebrand factor and COMP, respectively
2. Identification of novel cofactors that regulate ADAMTS13 and ADAMTS7 function under physiological conditions.
3. Development of novel diagnostic tools such as a fluorescent energy transfer (FRETS) assay for patients with thrombotic thrombocytopenic purpura or cardiovascular diseases.
4. Using murine models to understand the mechanisms of thrombotic thrombocytopenic purpura and to test therapeutic efficacy of novel therapies.
5. The role of ADAMTS13 and ADAMTS7 in atherosclerosis and inflammation.

CURRENT LAB PERSONNEL:

Shun Liang, M.D., Sr. Research Specialist
Veronica Casina, Ph.D. (Wake Forest Univ), Postdoctoral fellow;
Jialing Bao, Ph.D. (Penn State Univ), Postdoctoral fellow;
Brandy Pickens, Ph.D. (Temple Univ), Postdoctoral fellow;
Ying Y. Mao, Ph.D. (Temple Univ), Postdoctoral fellow;
Xiao-Hui Zhang, M.D., Ph.D. Visiting Scientist;
Hayley Hanby, CBP (Univ Penn), Graduate student;
Anastasia Lyalenko (Univ Penn), Undergraduate.

Description of Clinical Expertise

Director of Hematology and Coagulation Laboratories.

Areas of Interest:

Hemostasis and thrombosis,
Transfusion medicine,
Thrombotic thrombocytopenic purpura (TTP),
Hemolytic uremic syndrome (HUS),
Hemophilia and thrombophilia,
Platelet dysfunctions, and
Thrombotic/bleeding complications during pregnancy.

Description of Other Expertise

Editor-In-Chief,
Hereditary Genetics
Section Editor,
Archives of Pathology and Laboratory Medicine