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Guo-Ping Shi, MSc, DSc
Biochemist, Brigham and Women's Hospital
Associate Professor of Medicine, Harvard Medical School

Brigham and Women's Hospital
Department of Medicine
Cardiovascular
75 Francis Street
Boston, MA 02115


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Research Narrative:
My activities at Harvard Medical School (HMS) and Brigham and Women’s Hospital (BWH) focus solely on basic research. Directing and supervising undergraduate students, graduate students, clinical fellows, and post-doctoral research fellows is my main contribution to local communities. My primary research contributions to the global scientific community include leadership in the fields of cysteine protease cathepsins and mast cells in the pathogenesis of cardiovascular, metabolic, neurological, autoimmune, and renal diseases.
Cysteinyl cathepsins belong to the papain subfamily and contain 13 members, to which my colleagues and I have contributed 5 members. In the early years of my research (1990–2000), I worked with my Ph.D. advisor, Dr. Harold Chapman, and led the original identification and characterization of these novel proteases. We were one of the first groups to develop cathepsin-deficient mouse models for studying human diseases. Our early studies established the regulatory activity of several cathepsins during the pathogenesis of bone resorption and Alzheimer’s disease, and later in atherosclerosis, abdominal aortic aneurysms (AAAs), and cancer. For the last 18 years, I have led studies of cathepsins in vascular diseases with worldwide impact, and have published (mostly in highly-ranked journals such as The Journal of Clinical Investigation and Circulation) a series of research and review articles that established essential roles of individual cathepsins — such as S, K, and L — in atherosclerosis and AAAs, from human clinical studies to experimental models, and to their molecular and cellular mechanisms. We also have recently discovered the roles of these cathepsins in obesity and diabetes, and have published several seminal articles to lead this new field. Furthermore, our unpublished studies have revealed several previously unrecognized roles of cathepsins in systemic lupus erythematosus (SLE) and acute kidney injury, from which we have one R01 application submitted, one manuscript currently under consideration for publication in Nature, and another manuscript under preparation. Our studies in the field of cysteinyl cathepsins have led to the development of several small-molecule inhibitors that are currently in different phases of human clinical trials, and I have served as a Scientific Advisor of these studies. During the last 10 years, I have given 5 invited national presentations and 6 invited international presentations related to cathepsins. In this field, we have obtained five R01s, and I served as the Principal Investigator (PI) on two of these. I was also the PI on one American Heart Association (AHA) grant and on two private funds. I am a co-inventor on two issued U.S. patents in cathepsins and on three pending patent applications.
I am also internationally recognized in the field of mast cell (MC) functions in cardiovascular and metabolic diseases. Based on the fundamental studies of Drs. Petri Kovanen and Ken Lindstedt from Finland, we have led the demonstration of direct participation of MCs in atherosclerosis, AAAs, obesity, and diabetes. Using experimental models, we demonstrated that MCs release pro-inflammatory cytokines to activate inflammatory cells and vascular cells. Pharmacological inactivation of MCs reduces or prevents tissue inflammation and disease progression. Our series of articles in highly ranked seminal publications, including Nature Medicine, The Journal of Clinical Investigation, and Circulation, have opened a new field of basic and clinical research regarding MCs that has already shown benefits among patients. These studies have yielded us 4 R01s and an AHA Established Investigator Award, along with 2 patents, 4 invited local presentations, 4 nationally invited presentations, 30 internationally invited presentations, 6 media interviews, at least 2 television news reports, and more than 120 online news reports. Our recent studies in MCs focus on their functions in Alzheimer’s disease and SLE. Our preliminary studies have already yielded a NIH R01 application.
In addition to the two fields described above, we recently have discovered that cell channel protein Na-Cl channel co-transporter (NCC) serves as a novel receptor for interleukin-18 (IL18). This study is currently under consideration for publication in Nature Medicine. We received a 25th percentile score for its NIH/NHLBI R01 application A0 submission and 19% for A1 submission. We will repackage this proposal as a new submission this fall. The significance of this study is not limited to vascular diseases, but also encompasses other IL18-related inflammatory diseases and basic cell receptor biology.
My teaching activities at HMS focus on directing and supervising undergraduate students, graduate students, clinical fellows, and post-doctoral research fellows. Training includes project idea development, technical skills, manuscript and grant writing, laboratory compliance, collaboration skills, and data presentation skills. There is no clinical activity involved.

In summary, my teaching and research activities at HMS and BWH have focused on directing basic and clinical laboratory research in the fields of cysteine protease cathepsins and MCs in human cardiometabolic diseases. Besides training top quality physician scientists, we have made a series of discoveries, as reflected by continuous NIH and private grant/award support, top publications, numerous inventions, and invited national and international conference presentations. Our discoveries have led to the initiation of multiple human clinical trials (in the cathepsin field) and have benefited patients affected by vascular or metabolic diseases (in the mast cell field).


Education:
Harvard University, 1995, DSc
Beijing Agriculture University, 1987, MSc

Publications (Pulled from Harvard Catalyst Profiles):

1. Li J, Xia N, Wen S, Li D, Lu Y, Gu M, Tang T, Jiao J, Lv B, Nie S, Liao M, Liao Y, Yang X, Hu Y, Shi GP, Cheng X. IL (Interleukin)-33 Suppresses Abdominal Aortic Aneurysm by Enhancing Regulatory T-Cell Expansion and Activity. Arterioscler Thromb Vasc Biol. 2019 Mar; 39(3):446-458.

2. Pu C, Xu Y, Liu Q, Zhu A, Shi G. Enantiomers of Single Chirality Nanotube as Chiral Recognition Interface for Enhanced Electrochemical Chiral Analysis. Anal Chem. 2019 Feb 19; 91(4):3015-3020.

3. He A, Fang W, Zhao K, Wang Y, Li J, Yang C, Benadjaoud F, Shi GP. Mast cell-deficiency protects mice from streptozotocin-induced diabetic cardiomyopathy. Transl Res. 2019 Jan 19.

4. Wang Y, Liu CL, Fang W, Zhang X, Yang C, Li J, Liu J, Sukhova GK, Gurish MF, Libby P, Shi GP, Zhang J. Deficiency of mouse mast cell protease 4 mitigates cardiac dysfunctions in mice after myocardium infarction. Biochim Biophys Acta Mol Basis Dis. 2019 Jan 11.

5. Tang H, Cai D, Ren T, Xiong P, Liu Y, Gu H, Shi G. Fabrication of a low background signal glucose biosensor with 3D network materials as the electrocatalyst. Anal Biochem. 2019 Feb 15; 567:63-71.

6. Fang W, He A, Xiang MX, Lin Y, Wang Y, Li J, Yang C, Zhang X, Liu CL, Sukhova GK, Barascuk N, Larsen L, Karsdal M, Libby P, Shi GP. Cathepsin K-deficiency impairs mouse cardiac function after myocardial infarction. J Mol Cell Cardiol. 2019 Feb; 127:44-56.

7. Wang J, Cheng X, Xiang MX, Alanne-Kinnunen M, Wang JA, Chen H, He A, Sun X, Lin Y, Tang TT, Tu X, Sjöberg S, Sukhova GK, Liao YH, Conrad DH, Yu L, Kawakami T, Kovanen PT, Libby P, Shi GP. IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe-/- mice. J Clin Invest. 2018 Nov 01; 128(11):5184.

8. Wang Y, Liu CL, Lindholt JS, Shi GP, Zhang J. Plasma Cystatin B Association With Abdominal Aortic Aneurysms and Need for Later Surgical Repair: A Sub-study of the VIVA Trial. Eur J Vasc Endovasc Surg. 2018 Dec; 56(6):826-832.

9. Ouyang Q, Huang Q, Jiang Z, Zhao J, Shi GP, Yang M. Using plasma circRNA_002453 as a novel biomarker in the diagnosis of lupus nephritis. Mol Immunol. 2018 09; 101:531-538.

10. Chen ZH, Han XY, Deng LX, Lin ZY, Mu FY, Zhang S, Shi G, Zhang M. A self-calibrating logic system and oxidase-based biosensor using Tb3+-doped carbon dots/DNA conjugates. Talanta. 2019 Jan 01; 191:235-240.