My research focuses on the role of serine protease inhibitors in inflammation, sepsis, and cancer metastasis. Inter-alpha inhibitors (IaI) are a family of complex proteins known to inhibit serine proteases such as trypsin, elastase, and plasmin. Significant decrease of IaI levels is found in septic patients and the levels correlate inversely with disease severity and mortality. The long term goal is to develop IaI as a useful theranostic marker and a therapeutic agent in sepsis and cancer.
My research focuses on the role of natural serine protease inhibitors in inflammation, sepsis/shock, and cancer metastasis. Inter-alpha inhibitors (IaI) are a family of complex glycoproteins composed of several polypeptide chains linked uniquely by glycosaminoglycan. IaI are known to inhibit several serine proteases such as trypsin, human leukocyte elastase (HLE), plasmin, cathepsin G, and granzyme K which are involved in inflammation, shock, tumor invasion, and formation of metastases. Recently we have also demonstrated that IaI inhibit furin, a key enzyme that cleaves anthrax toxin. We have found that the IaI levels decrease significantly in adult patients and newborns with sepsis and the levels correlate inversely with disease severity and mortality. The long term goal is to develop IaI as a theranostic marker and a therapeutic agent in deadly diseases such as sepsis and cancer metastasis. Highly purified IaI from plasma appear to be a useful and safe agent for maintaining hemodynamic stability, preventing organ injury, and improving survival in sepsis patients and those exposed to agents likely to induce a "cytokine storm." We have established experimental models in adult and newborn animals to study the protective mechanism of IaI in systemic inflammation and sepsis. Furthermore, in an in vitro 3-dimensional cell invasion assay, IaI effectively inhibit the migration of human tumor cells. Addition of specific monoclonal antibody against IaI (MAb 69.31) specifically blocks the inhibitory activity of IaI in this assay. These results have led us to evaluate the potential therapeutic use of this serine protease inhibitor in inhibiting metastasis in vivo.
2/93-2/94 Rhode Island Foundation Medical Research Grant
"Assay development for detection of early stages of colon cancer." Yow-Pin Lim, P.I.
Total direct $4,085.
5/93-6/94 Roger Williams Core Grant #CA13943-20
"Monoclonal Antibodies detecting circulating antigens in colon cancer". Yow-Pin Lim, P.I.
Total direct $6,830
6/94-6/95 American Cancer Society Institutional Research Grant, ACS IN-45-35.
"Circulating Immune Complexes in Breast and Colon Cancer". Yow-Pin Lim, P.I.
Total direct $7,850.
12/93-12/96 Amgen, Inc.
Amgen Cancer Research Fellowship, Awarded to Yow-Pin Lim.
Total direct $120,000 - Annual direct $40,000.
12/94-11/98 National Cancer Institute (NCI) Grant R01 CA42714
"Molecular determinants of Multicellular Origin". Douglas. C. Hixson, PI, Yow-Pin Lim, Co-Inv.
Total direct $543,815 - Annual direct $121,790.
11/95-10/96 Octapharma Pharmaceutical, Vienna, Austria, Contract "Epitope Mapping of Factor VIII". Douglas. C. Hixson, PI, Yow-Pin Lim, Co-P.I.
Total direct $48,250.
07/95-06/96 Pliva Research Institute, Croatia, Contract
"Isolation, Purification and Cloning of Gastric Peptide BPC". Douglas. C. Hixson, PI, Yow-Pin Lim, Co-P.I.
Total direct $82,360.
05/99-01/04 NCI Grant R01 CA42714
"Molecular determinants of Multicellular Origin". Douglas. C. Hixson, PI, Yow-Pin Lim, Co-Inv. Annual
Total direct $191,124.
09//02-08//03 Slater Center for Biomedical Technology.
"Therapeutic and Prognostic Application Of Human Plasma Inter-alpha Inhibitor in the Management of Sepsis". Yow-Pin Lim, PI.
Total direct $80,000.
03/02-03/03 NIH/ National Institute of General Medical Sciences (NIGMS) Small Business Innovation Research (SBIR) Phase I, 1R43GM65667-01
Therapeutic Use of Inter-alpha Inhibitor In Sepsis. Yow-Pin Lim, PI.
Total direct $99,069
04/02-03/03 Lifespan Developmental Grant.
Immunoregulatory Role of Granzyme in Sepsis". Yow-Pin Lim, PI.
Total direct $30,000.
05/03-05/04 NIH/NIGMS SBIR Phase I, 1 R43 GM068171-01
"Predictive Value of Inter-alpha Inhibitor In Sepsis". Yow-Pin Lim, PI.
Total direct $91,000.
04/04-03/05 Centers of Biomedical Research Excellence (COBRE) Translational Research grant award.
"Role of Inter-alpha inhibitors in Cancer Metastasis. Yow-Pin Lim, PI.
Total direct $25,000.
07/04-06/07 NIH/NIGMS SBIR Phase II, 2R44GM65667-02
"Therapeutic Use of Inter-alpha Inhibitor In Sepsis". Yow-Pin Lim, PI.
Total direct $1,150,375.
07/04-12/06 NIH/ National Institute of Child Health and Human Development (NICHD) Exploratory/Development Grant, 1 R21 HD047600-01
"Inter-alpha Inhibitors in Neonatal Sepsis". Yow-Pin Lim, PI.
Total direct $275,000.
06/05-12/06 NIH/NCI SBIR Phase I, 1R43 CA110698-01
"Inter-alpha Inhibitors in CNS Cancer", Yow-Pin Lim, PI.
Total direct $99,925.
05/06-04/08 NIH/ National Institute of Allergy and Infectious Diseases (NIAID)
Small Business Technology Transfer (STTR) Phase I, 1 R41 AI062095-01A2
"Role of Inter-alpha Inhibitors in Anthrax Intoxication", Yow-Pin Lim, co-PI.
Total direct $1,000,000.
06/06-05/07 COBRE Center for Cancer Research Development (CCRD)
Pilot Project: Inter-alpha Inhibitors as Theranostic Markers and Preventative Agent for Septic Complication in Cancer" Yow-Pin Lim, PI.
Total direct $43,750.
