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David Griggs, Ph.D.

Associate Professor
Molecular Microbiology and Immunology


Education

Post-Doctoral Fellowship, Washington University in St. Louis
Ph.D. in Microbiology, University of Illinois, 1989

Research Interests

My laboratory specializes in the translation of basic discoveries to therapeutic application for rare and neglected diseases. We are currently applying our molecular, cellular, and pharmacology expertise in collaborative efforts to develop new medicines for treatment of organ fibrosis, bone disorders, cryptosporidiosis, and tuberculosis. We perform target validation, assay development and optimization for high-throughput screening of compounds, assessment of target potency and selectivity for lead characterization, in vitro and in vivo ADME (drug pharmacokinetics and metabolism), and the development of biomarker assays that promote the advancement of projects from preclinical phase to human clinical testing.

One project in my laboratory explores how a particular subset of the family of cell surface proteins called integrins contributes to the process of fibrosis (scar formation) that promotes tissue destruction and loss of organ function in many human diseases. We use novel small molecule integrin inhibitors, antibodies, and other tools to assess effects on molecular and cellular phenotypes in vitro. We also collaborate to evaluate the effects of compound treatments in models of human pathologies such as acute and chronic kidney disease, non-alcoholic steatohepatitis (NASH), chronic pancreatitis, skeletal and cardiac muscle fibrosis, cancer, and idiopathic pulmonary fibrosis.

Another project is attempting to elucidate the pharmacokinetic and pharmacodynamic properties of compounds which are most important for activity in killing Cryptosporidium. This parasite is the causative agent of cryptosporidiosis, an illness that often causes life-threatening diarrhea in infants worldwide, incurable diarrhea in AIDS and transplant patients, and is the most common cause of waterborne diarrheal outbreaks in the United States and Europe.  There is a critical need for new drugs to treat cryptosporidiosis, but there is poor understanding of what a good treatment should look like at the preclinical stage.  Leading researchers throughout the world have provided us with diverse compounds which we are systematically profiling to determine which properties are associated most closely with efficacy.

My laboratory is collaborating on several drug discovery projects involving high throughput screening.  One is a partnership with Rajeev Aurora (Saint Louis University), and seeks to identify and develop compounds capable of mimicking the effect of low dose RANKL treatment in preventing bone loss through a novel immunologic mechanism. If the project is successful, such agents could be useful in treatment of rare bone disorders such as osteogenesis inperfecta and some congenital forms of osteopetrosis, and ultimately may impact the treatment of much more common conditions such as osteoporosis.  Another screening project, a collaboration with Christina Stallings (Washington University), seeks to identify and develop compounds that inhibit a bacterial enzyme activity that is essential for pathogenesis of Mycobacterium tuberculosis. This bacterium, which infects approximately one third of the world’s population and causes an estimated 1.8 million deaths a year, is increasingly resistant to the few antibiotics used for treatment. New drugs are urgently needed. My laboratory supported the development and performance of the novel screening assay, and is characterizing the pharmacologic properties of hits with therapeutic potential. Similarly, we are collaborating with other members of our department to help characterize the pharmacology of antiviral compounds.


Grants

ACTIVE

NIH-R01 AR068438-01
Title: High throughput screening to identify small molecule RANK agonists.
Role: Principle Investigator
Period: 08/15 – 07/19     

NIH-R33 AI111696-03     
Title: Targeting a new essential virulence mechanism of drug-resistant mycobacteria.   
Role: Co-Investigator    
Period: 03/16 – 02/19  

NIH/NCATS U54TR001961-01 
Title: Washington University Institute of Clinical and Translational Sciences   
Role: Site Associate Director    
Period: 06/17- 5/22 

The Bill and Melinda Gates Foundation OPP1161880
Title: Pharmacokinetic and pharmacodynamic profiling of compounds with known anti-Cryptosporidial activity.
Role: Principle Investigator
Period: 06/17 – 05/19 

Indalo Therapeutics, Inc., Sponsored Services Agreement
Title: Characterization of integrin antagonists in cell- and tissue-based assays.
Role: Principle Investigator 
Period: 07/17 – 12/19

St. Louis VA Medical Center IO1 BX003674
Title: Mechanisms and treatment of kidney fibrosis.
Role: Co-Investigator
Period: 01/18 – 12/19

Publications and Media Placements

Stebbins, E. R.S. Jumani, C. Klopfer, J. Barlow, P. Miller, M.A. Campbell, M.J. Meyers, D.W. Griggs, C.D. Huston. 2018. Clinical and microbiologic efficacy of the piperadine-based drug lead MMV665917 in the dairy calf cryptosporidiosis model. PLoS Negl Trop Dis. 12(1):e0006183.  PMID: 29309415

Murray, I.R., Z.N. Gonzalez, J. Baily, R. Dobie, R.J. Wallace, A.C. Mackinnon, J.R. Smith, S.N. Greenhaigh, A.I. Thompson, K.P. Conroy, D.W. Griggs, P.G. Ruminski, G.A. Gray, M. Singh, M.A. Campbell, T.J. Kendall, J. Dai, Y. Li, J.P Iredale, H. Simpson, J. Huard, B. Peault, N.C. Henderson. 2017. Alpha v integrins on mesenchymal cells critically regulate skeletal and cardiac muscle fibrosis. Nature Commun. 8(1):1118.  PMID:  29061963

Griggs, D.W., M.J. Prinsen, J. Oliva, M.A. Campbell, S.D. Arnett, D. Tajfirouz, P.G. Ruminski, Y. Yu, B.R. Bond, Y. Ji, G. Neckermann, R.K.M Choy, E. de Hostos, M.J. Meyers. 2016. Pharmacologic comparison of clinical neutral endopeptidase inhibitors in a rat model of acute secretory diarrhea. J Pharmacol Exp Ther 367:423-431.  PMID:  26907621

Ulmasov, B., B.A. Neuschwander-Tetri, J. Lai, V. Monastyrskiy, T. Bhat, M. Yates, J. Oliva, M.J. Prinsen, P. Ruminski, D.W. Griggs. Targeted pharmacologic inhibition of RGD-binding integrins suppresses pancreatic fibrosis in mice. 2016. Cell Mol Gastroenterol Hepatol 2:499-518.  PMID:  27324129

Meyers, M.J., E.J. Anderson, S.A. McNitt, T.M. Krenning, M. Singh, J. Xu, W. Zeng, L. Qin, C.S.. Eickhoff, J. Oliva, M.A. Campbell, S.D. Arnett, M.J. Prinsen, D.W. Griggs, P.G. Ruminski, D.E. Goldberg, K. Ding, X. Liu, Z. Tu, M.D. Tortorella, F. M, Sverdrup, and X. Chen. Evaluation of spiropiperadine hydantoins as a novel class of antimalarial agents. 2015. Bioorg Med Chem 23:5144-5150.  PMID:  25979165

Meyers, M.J., M.D. Tortorella, J. Xu, L. Qin, Z. He, X. Lang, W. Zeng, W. Xu, L. Qin, M.J. Prinsen, F.M. Sverdrup, C.S. Eickhoff, D.W. Griggs, J. Oliva, P.G. Ruminski, E.J. Jacobsen, M.A. Campbell, D.C. Wood, D.E. Goldberg, X. Liu, Y. Chen, Z. Tu, X. Lu, K. Ding, and X. Chen. 2013. Evaluation of aminohydantoins as a novel class of antimalarial agents. 2014. ACS Med. Chem. Lett. 5:89-93.  PMID:  24900778

Henderson, N.C., T.D. Arnold, Y. Katamura, M.M. Giacomini, J.D. Rodriquez, J.H. McCarty, A. Pellicoro, A.C. Mackinnon, P.G. Ruminski, D.W. Griggs, M.J. Prinsen, J.J. Maher, J.P. Iredale, A. Lacy-hulbert, R.H. Adams, and D. Sheppard. 2013. Targeting v integrin identifies a core molecular pathway that regulates fibrosis in several organs.  Nature Medicine. 19:1617-1624  PMID: 24216753

Chai, D.H., E.C. Arner, D.W. Griggs, and A.J. Grodzinsky. 2009. av and b1 integrins regulate dynamic compression-induced proteoglycan synthesis in 3D gel culture by distinct complementary pathways. Osteoarthritis and Cartilage, 18:249-256.  PMCID: 19800448

Zack, M.D., A-M Malfait, A.P. Skepner, M.P. Yates, D.W. Griggs, T. Hall, R.L. Hills, J.T. Alston, O.V. Nemirovskiy, M.R. Radabaugh, J.W. Leone, E.C. Arner, and M.D. Tortorella. 2009. ADAM-8 isolated from human osteoarthritic chondrocytes is capable of cleaving fibronectin at Ala271. Arthritis Rheum. 60:2704-2713.  PMID: 19714641

Hall, T, J.W. Leone, J.F. Weise, D.W. Griggs, G.E. Pegg, A.M. Pauley, A. Tomaselli, and M.D. Zack.  2009.  Auto-activation of human ADAM8: a novel preprocessing step is required for catalytic activity. BioScience Reports 29:217-228.  PMID: 18811590

Malfait, A.M., E.C. Arner, R.H. Song, J.T. Alston, S. Markosyan, N. Staten, Z. Yang, D.W. Griggs, M.D. Tortorella. 2008. Proprotein convertase activation of aggrecanases in cartilage in situ. Arch. Biochem. Biophys. 478:43-51.  PMID: 18671934

Nagarajan, A.R., B. Devadas, J.W. Malecha, H-F Lu, P. Ruminski, J.G. Rico, T.E. Rogers, L.D. Marrufo, J.T. Collins, H.P. Kleine, M.K. Lantz, J. Zhu, N.F. Green, M.A. Russell, B.H. Landis, L.M. Miller, D.M. Meyer, T.D. Duffin, V.W. Engleman, M.B. Finn, S.K. Freeman, D.W. Griggs, M.L. Williams, M.A. Nickols, J.A. Pegg, K.E. Shannon, C. Steininger, M.M. Westlin and J.L. Keene. 2007. R-isomers of Arg-Gly-Asp (RGD) mimics as potent v3 inhibitors. Bioorg. Med. Chem. 15:3783-3800.  PMID: 16492166

Song, R-H, M.D. Tortorella, A-M Malfait, Z. Yang, E.C. Arner, and D.W. Griggs. 2007. Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum. 56:575-585.  PMID: 19714641