DEGREE (if applicable)

Size: px

Start display at page:

Download "DEGREE (if applicable)"

Melvyn Lyons
5 years ago
Views:

1 NAME: Jiang, Dianhua OMB No /0002 (Rev. 08/12 Approved Through 8/31/2015) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. era COMMONS USER NAME (credential, e.g., agency login): DIANHUAJ POSITION TITLE: Research Scientist III / Professor EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) INSTITUTION AND LOCATION DEGREE (if applicable) Completion Date MM/YYYY FIELD OF STUDY Shandong Medical University, Ji nan, China Bachelor of 08/1984 Medicine Medicine Medical University of Ohio, Toledo, Ohio Ph.D. 12/1996 Biochemistry and Molecular Biology Yale University School of Medicine, New Haven, CT Postdoctoral training 07/2000 Lung Injury and Repair I. Personal Statement The current proposal is address the roles of HA, HAS2, and CD44 in regulating the development of pulmonary fibrosis and liver fibrosis. We will use state-of-the-art technology to test our hypothesis that targeting CD44 is an effective treatment in severe pulmonary fibrosis. I was trained in molecular biology and lung biology, and have long interest in lung fibrosis. My laboratory has defined the roles of the glycosaminoglycan hyaluronan and its receptor, CD44 in regulating lung inflammation and fibrosis in response to non-infectious lung injury. My lab has extensive experience in generating genetically modified mouse models. As PI and co-pi on several NIH-funded grants, I have expanded my experience not only on my own research in the field of molecular pulmonary medicine, but also on collaboration with other investigators, management of research projects, and on the training and management of postdoctoral researchers and research technicians. I have been very fortunate to publish several high profile studies. In summary, I have a sound career record of successful and productive research, and my education and experience have prepared me to succeed in the proposed study. (1) Jiang, D., Liang, J., Juan Fan, Shuang Yu, Suping Chen, Yi Luo, Glenn D. Prestwich, Robert J. Homer, Daniel R. Goldstein, Ruslan Medzhitov, and Paul W. Noble. Regulation of Lung Inflammation and Repair By Toll-like Receptors and Hyaluronan. Nature Medicine Nov;11(11): PMID: (2) Dong Y, Geng Y, Li L., Li, X., Yan X., Fang Y., Li, X., Dong S, Liu, X., Li, X., Yang X, Zheng X., Xie T., Liang J., Dai H., Yin Z, Noble PW, Jiang D*, Ning W*. Blocking FSTL1 attenuates pulmonary fibrosis in mice. J Exp Med : (doi: /jem ). PMID: PMCID: PMC (3) Jiang D*, Liang J, Campanella GS, Guo R, Yu S, Xie T, Liu N, Jung Y, Homer R, Meltzer EB, Li Y, Tager AM, Goetinck PF, Luster AD, Noble PW*. Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4. J Clin Invest Jun 1;120(6): PMID: ; PMCID: PMC (4) Jiang, D*. Liang, J., and Noble P.W*. Hyaluronan as an Inflammatory Regulator in Human Diseases. Physiological Review Jan;91(1): PMID: , PMCID: PMC

2 II. Positions and Honors Positions and Employment Medical Internship, Shandong Medical University, China Teaching Assistant in Anatomy and Cell Biology, Beijing University of Chinese Medicine, Beijing, China Lecturer in Anatomy and Cell Biology, Beijing University of Chinese Medicine, Beijing, China Postdoctoral Associate, Yale University School of Medicine Section of Pulmonary and Critical Care Medicine, New Haven, CT Associate Research Scientist, Yale University School of Medicine Section of Pulmonary and Critical Care Medicine, New Haven, CT Staff Scientist, Genetica Inc., Cambridge, MA Research Scientist, Curagen Corporation, New Haven, CT Associate Research Scientist, Yale University School of Medicine Section of Pulmonary and Critical Care Medicine, New Haven, CT Assistant Professor of Medicine, Yale University School of Medicine Section of Pulmonary and Critical Care Medicine, New Haven, CT Associate Professor of Medicine, Duke University School of Medicine Division of Pulmonary, Allergy & Critical Care Medicine, Durham, NC 2013-present Research Scientist III/Professor, Department of Medicine and Women s Guild Lung Institute, and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA Other Experience and Professional Memberships 2000 Member, American Thoracic Society 2009 Member, American Physiological Society 2009 Member, Society for Clinical and Translational Science 2012 President ( ), Chinese-American Lung Association 2013 Member, Society for Glycobiology C. Contribution to Science a. Extracellular Matrix Hyaluronan in Lung Injury and Fibrosis. During the last 18 years, we have characterized the role of hyaluronan in the setting of lung injury and lung fibrosis. We have shown that the adhesion molecule CD44 is necessary for hematopoietic cells to clear HA from sites of lung inflammation. This work was published in Science in How does glycosaminoglycan hyaluronan regulate lung injury? We found that hyaluronan fragments interact with TLR4 and TLR2 on both epithelial cells and macrophages to differentiate the function of this interaction on different cell types during non-infectious tissue injury. We were the first to identify the existence of an endogenous ligand for TLRs, and also demonstrated that the extracellular matrix-tlr interactions orchestrate the inflammatory response during non-infectious lung injury as well as epithelial cell integrity and survival. The seminal study was published in Nature Medicine in 2005 and received broad attention, rated as Exceptional by Faculty1000, and cited more than 800 times. 1 Teder, P., Vandivier, R.W., Jiang, D., Liang, J., Cohn, L., Pure, E., Henson, P.M., and Noble, P.W. Resolution of lung inflammation by CD44. Science : PMID: Jiang, D., Liang, J., Juan Fan, Shuang Yu, Suping Chen, Yi Luo, Glenn D. Prestwich, Robert J. Homer, Daniel R. Goldstein, Ruslan Medzhitov, and Paul W. Noble. Regulation of Lung Inflammation and Repair By Toll-like Receptors and Hyaluronan. Nature Medicine Nov;11(11): PMID: Liang, J., Jiang, D., Jung, Y., Xie, T., Ingram, J., Church, T., Degan, S., Leonard, M., Kraft, M., and Noble, P.W Role of hyaluronan and hyaluronan-binding proteins in human asthma. J Allergy Clin Immunol 128: e403. PMCID Jiang D, Liang J, Noble PW. Hyaluronan in Tissue Injury and Repair. Annu Rev Cell Dev Biol : (2006 Sep 8; [Epub ahead of print]) PMID: Jiang, D*. Liang, J., and Noble P.W*. Hyaluronan as an Inflammatory Regulator in Human Diseases. Physiological Review Jan;91(1): PMID: , PMCID: PMC b. Role of Follistatin-like 1 in Lung Development and Lung Fibrosis. We recently defined the role of follistatin-like 1 (Fstl1) in regulation of lung development (PNAS 2011), and in lung fibrosis (JEM 2015). We

3 found that FSTL1 acts as a BMP antagonist to regulate bronchial formation and alveolar maturation. In lung injury model, FSTL1 promotes TGFbeta signaling in both epithelial cells and fibroblasts, whereas FSTL1 antagonizes BMP signaling only in epithelial cells, not in fibroblasts. We further showed that a neutralizing antibody against Fstl1 was able to modulate lung fibrosis in vivo by regulating TGFbeta/BMP signaling pathways. We are developing humanized neutralizing antibodies with the hope to develop therapeutics for patients with severe pulmonary fibrosis. 6. Geng Y, Dong Y, Yu M, Zhang L, Yan X, Sun J, Qiao L, Geng H, Nakajima M, Furuichi T, Ikegawa S, Gao X, Chen YG*, Jiang D*, Ning W*. Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development. Proc Natl Acad Sci U S A Apr : PMID: ; PMCID: PMC Dong Y, Geng Y, Li L., Li, X., Yan X., Fang Y., Li, X., Dong S, Liu, X., Li, X., Yang X, Zheng X., Xie T., Liang J., Dai H., Yin Z, Noble PW, Jiang D*, Ning W*. Blocking FSTL1 attenuates pulmonary fibrosis in mice. J Exp Med : (doi: /jem ). PMID: PMCID: PMC c. Role of Chemokines in Lung Injury and Fibrosis. We discovered that the deletion of chemokine receptor CXCR3 resulted in exaggerated lung fibrosis attributed to the lack of early interferon-gamma burst after lung injury. It is well documented that interferon-gamma is able to inhibit tissue fibrosis in animal models. Furthermore, we discovered that CXCL10 protects against mouse death caused by bleomycin and inhibits fibroblast migration by interacting with syndecan-4, not its cognate receptor CXCR3, on fibroblasts. We demonstrated that the chemokine mutants contain a heparin-binding domain function to reduce lung fibrosis without inflammation, suggesting a novel therapeutic target. These studies were published in the Journal of Clinical Investigation in 2004 and 2010, respectively. The latter article was evaluated by Faculty of 1000 and covered by SciBX. 8 Jiang, D., Liang, J., Hodge, J., Lu, B., Zhu, Z., Yu, S., Fan, J., Yin, Z., Homer, R., Gerard, C., Noble, P.W. Regulation of Pulmonary Fibrosis by Chemokine Receptor CXCR3. J Clin Invest (2): PMID: ; PMCID: PMC Jiang D*, Liang J, Campanella GS, Guo R, Yu S, Xie T, Liu N, Jung Y, Homer R, Meltzer EB, Li Y, Tager AM, Goetinck PF, Luster AD, Noble PW*. Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4. J Clin Invest Jun 1;120(6): PMID: ; PMCID: PMC Jiang, D., Liang, J., Guo, R., Xie, T., Kelly, F.L., Martinu, T., Yang, T., Lovgren, A.K., Chia, J., Liu, N., et al Long-term exposure of chemokine CXCL10 causes bronchiolitis-like inflammation. Am J Respir Cell Mol Biol 46: PMCID d. Role of Fibroblast Invasion in Lung Fibrosis. We recently discovered that fibrotic fibroblasts display an invasive phenotype which is regulated by hyaluronan synthase-2 and hyaluronan receptor CD44. Blocking hyaluronan synthase-2 and CD44 attenuated lung fibrosis. We further determined that adaptor protein betaarrestins play a role in the process. These studies identified that the extracellular components hyaluronan, HAS2, and CD44, as well as beta-arrestin signaling can be valid therapeutic targets for progressive lung fibrosis. 11. Lovgren AK, Kovacs JJ, Xie T, Potts EN, Li Y, Foster WM, Liang J, Meltzer EB, Jiang D, Lefkowitz RJ, Noble PW. {beta}-arrestin Deficiency Protects Against Pulmonary Fibrosis in Mice and Prevents Fibroblast Invasion of Extracellular Matrix. Science Transl Med Mar 16;3(74):74ra23. PMID: PMID: ; PMCID: PMC Li, Y., D. Jiang, J. Liang, E. B. Meltzer, A. Gray, R. Miura, L. Wogensen, Y. Yamaguchi, and P. W. Noble Unrelenting Lung Fibrosis Requires an Invasive Myofibroblast Phenotype Regulated by Hyaluronan and CD44. J Exp Med Jul 4;208(7): PMID: ; PMCID: PMC e. Role of microrna in Lung Injury and Lung Fibrosis. We are also studying the role of microrna in lung injury and repair, by examining microrna expression pattern during tissue injury and generating genetically modified mice targeting specific mirnas. 13. Xie T, Liang J, Guo R, Liu N, Noble PW, Jiang D*. Comprehensive microrna analysis in bleomycininduced pulmonary fibrosis identifies multiple sites of molecular regulation. Physiol Genomics May 13;43(9): PMID: ; PMCID: PMC

4 14. Xie, T., Liang, J., Liu, N., Wang, Q., Li, Y., Noble, P.W., and Jiang, D* MicroRNA-127 inhibits lung inflammation by targeting IgG Fcgamma receptor I. J Immunol 188: PMID: ; PMCID: PMC D. RESEARCH SUPPORT Current Support 1. R01 HL Dianhua Jiang (Contact PI) and Paul W. Noble (PI). NIH/NHLBI. 1/ /2018 Targeting beta-arrestins in Pulmonary Fibrosis. This proposal focuses on elucidating the roles of b-arrestins (barr1 and barr2) in regulating lung inflammation and fibrosis and to determining the feasibility that targeting b-arrestins as a novel therapeutic approach for lung fibrosis. 2. P01 HL108793, Paul W. Noble (PI), 07/ /2017. NIH/NHLBI Project I, Matrix regulation of fibroproliferative lung disease Role: Co-PI Host factors in regulation of inflammatory and fibroproliferative lung disease The goal of this proposal is to provide mechanistic insights into how endogenous host factors regulate chronic inflammation, airway remodeling and interstitial fibrosis in mouse and man. 3. P01 HL108793, 07/ /2017. NIH/NHLBI Animal and sample analysis core Role: PI Host factors in regulation of inflammatory and fibroproliferative lung disease The purpose of Mouse Model Core is to provide a resource and analysis for the PPG investigators to achieve the goal of the PPG: providing mechanistic insights into how endogenous host factors regulate chronic inflammation, airway remodeling and interstitial fibrosis in mouse and man. 4. R01 HL , Paul W. Noble (PI), 07/ /2016. NIH/NHLBI Mechanisms of Macrophage Activation in Lung Inflammation This proposal is to examine the role of hyaluronan, CD44 and TLRs in regulating lung inflammation and fibrosis 5. RB , Paul W. Noble (PI), 03/ /2016. CIRM Innate Immune Regulation of Lung Alveolar Stem Cell Renewal in Mouse and Man This study explores the proper renewal of lung stem cells requires the communication between an extracellular matrix sugar on the stem cell surface with an innate immune receptor, Toll-like receptor 4 with the goal of finding ways to promote lung stem cell renewal and treat patients with pulmonary fibrosis. 6. R01HL123899, Cory Hogaboam (PI), 09/ /2019. NIH/NHLBI Innate DNA Sensing In Rapidly Progressing IPF. The proposal will address the molecular mechanisms through which primary human fibroblasts are activated by exogenous hypomethylated DNA, and will seek to identify therapeutic strategies that interrupt this process during the exacerbation or rapid progression of pulmonary fibrosis. Past Support 1. R01 HL (PI: Paul W. Noble) 9/2003-8/2007 NIH/NHLBI Survivin Regulation of Lung Fibrosis 2. P50-HL (PI: Jo Rae Wright) 09/ /2011 NIH/NHLBI Project 4: Host Factors in Chronic Lung Diseases 3. R01 HL , Paul W. Noble (PI), 07/ /2014. NIH/NHLBI Regulation of Pulmonary Fibrosis by CXCR3 Role: Co-PI

5 PENDING (NONE)

DEGREE (if applicable) NOTE: The Biographical Sketch may not exceed five pages. Follow the formats and instructions below.

DEGREE (if applicable) NOTE: The Biographical Sketch may not exceed five pages. Follow the formats and instructions below. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format