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Douglas S. Darling, Ph.D.

 Name: Douglas S. Darling, Ph. D.

Title: Professor

Current Positions:
Department of Oral Health and Rehabilitation
Oral Health and Systemic Disease Research Group,
Birth Defects Center,
Center for Genetics and Molecular Medicine, and
Center for Environmental Genetics and Integrative Biology


Phone: 502-852-5508

E-mail: douglas.darling@louisville.edu

Background

University Degree Year(s)
George Washington Univ., Washington, D.C. B.S. 1977
University of Washington, Seattle, WA
Ph. D. 1983
University of Chicago Medical School, Chicago, IL Postdoc 1983-87
Harvard University + Howard Hughes Medical Inst., Boston
Postdoc 1987-92   



Research Interests and Current Projects (brief description)

Understanding the differentiation of salivary cells is a necessary step to enable the restoration of diseased or destroyed parotid salivary tissue. We are using gene expression arrays of differentiating salivary glands to identify networks that cause terminal differentiation. We study the relation between changes of microRNAs and mRNAs during differentiation.  Computer modeling is expected to have the capacity to test the relative importance of specific pathways within the networks, allowing validation by laboratory work.

We are also studying the molecular basis for trafficking of secreted proteins within the cell during regulated secretion.  We use a novel model for sorting of salivary proteins in which Parotid Secretory Protein (PSP) binds the membrane at phosphatidylinositol bisphosphate.  

Separately, our laboratory is interested in the regulation of gene transcription in eucaryotic cells. Current projects investigate the role of ZEB and related genes in early development, and the molecular interactions that underlie those roles.  We focus on development of the eye, which has specific defects in ZEB1-mutant mice that mimic birth defects in some human babies.  In addition, we are studying the molecular basis for cleft palate in ZEB1 knock-out mice.



Teaching Activities
Introduction to Oral Biology Research, (OBIO 601)
Oral Health Seminars, (OBIO 605)
Pathomedicine,  (IDSC 821-34)


Service (current and last three years)
NIH NIDCR ZDE1 MH (14) RFA Special Review Panel, 2012
NIH CSR ZRG1 MOSS-C (02) S - Musculoskeletal, Oral and Skin, 2010
Portuguese Foundation for Science and Technology, Ad Hoc Reviewer, 2009
NIH CSR ZRG1 MOSS-E (02)M, ODCS Member Conflict Special Panel, 2009
UofL Office of Research Integrity, Associate Research Integrity Ombudsperson 2010-
Center for Environmental Genomics and Integrative Biology (CEGIB), 2006 - 2011
CEGIB Internal Advisory Board (Executive Committee) 
ULSD Research Committee

Laboratory Members
Diana M. Blau
Melissa A. Metzler
Sara M. Perez
Ian S. Pyle


Publications (last 5 years)

  1. S.G. Venkatesh, J. Tan, S.U. Gorr and D.S. Darling (2007) Isoproterenol Increases Sorting Of Parotid Gland Cargo Proteins To The Basolateral Pathway. Am J Physiol Cell Physiol. 293: C558 - C565.   PMC2084485.
  2. Manavella PA,  Roqueiro G, Darling DS, and Cabanillas AM. (2007) The ZFHX1A gene is differentially autoregulated by its isoforms. Biochem. Biophys. Res. Commun. 360(3): 621-626.  doi:10.1016/j.bbrc.2007.06.088.  PMC2770808.
  3. Liu, Y., Costantino, M.E., Durango-Montoya D., Darling, D.S., and Dean, D.C. (2007)  The zinc finger transcription factor ZFHX1A is linked to cell proliferation through the Rb/E2F pathway.  Biochem. J. 408(1): 79-85.  PMCID: PMC2049079.
  4. Liu, Y., El-Naggar, S., Darling, D.S., Higashi, Y., and Dean, D.C.  (2008) Zeb1 links epithelial-mesenchymal transition and cellular senescence.  Development 135, 579-588.  doi:10.1242/10.1242/dev.007047.  PMC2507753. 
  5. Jin JZ, Li Q, Higashi Y, Darling DS, and Ding J (2008) Analysis of Zfhx1a mutant mice reveals palatal shelf contact-independent medial edge epithelial differentiation during palate fusion.  Cell and Tissue Research, 333:29-38. PMC2516965.
  6. M Singh, NS Spoelstra, A Jean, E Howe, KC Torkko, HR Clark, DS Darling, KR Shroyer, KB Horwitz, RR Broaddus, and JK Richer  (2008) ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease.  Mod Pathol. 21(7): 912-23.  PMID 18487993. 
  7. Yongqing Liu, Xiaoyan Peng, Jinlian Tan, Douglas S. Darling, Henry J. Kaplan, and Douglas C. Dean (2008) Zeb1 Mutant Mice as a Model of Posterior Corneal Dystrophy. Invest. Ophthalmol. Vis. Sci., 49: 1843-1849.  PMC2504018.
  8. Yongqing Liu, Fei Ye, Qiutang Li, Shigeo Tamiya, Douglas S. Darling, Henry J. Kaplan, and Douglas C. Dean (2009) Zeb1 Represses Mitf and Regulates Pigment Synthesis, Cell Proliferation, and Epithelial Morphology. Invest. Ophthalmol. Vis. Sci., 50: 5080 - 5088.  doi:10.1167/iovs.08-2911
  9. U. Wellner, J. Schubert, U.C. Burk, O. Schmalhofer, F. Zhu1, A. Sonntag, B. Waldvogel, C. Vannier, D.S. Darling, A.z. Hausen, V.G. Brunton, J. Morton, O. Sansom, J. Schüler, M.P. Stemmler, C. Herzberger, U. Hopt, T. Keck, S. Brabletz, T. Brabletz.  (2009) The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nature Cell Biology, 11(12): 1487-95.  PMID: 19935649
  10. JZ Jin, M Tan, DR Warner, DS Darling, Y Higashi, T Gridley, and J Ding. (2010)
    Mesenchymal cell remodeling during mouse secondary palate reorientation.
    Dev Dyn, 239(7): 2110-2117, PMC2919369.
  11. Kenney, P. A., Wszolek, M. F., Rieger-Christ, K. M., Neto, B. S., Gould, J. J., Harty, N. J., Mosquera, J. M., Zeheb, R., Loda, M., Darling, D. S., Libertino, J. A. and Summerhayes, I. C. (2010) Novel ZEB1 expression in bladder tumorigenesis. BJU International, 107(4): 656-63.  doi: 10.1111/j.1464-410X.2010.09489.x    
  12. SG Venkatesh, D Goyal, AL Carenbauer, and DS Darling. (2011) Parotid secretory protein binds Phosphatidylinositol (3,4)bisphosphate. J. Dental Research, 90(9): 1085 – 1090.  DOI 10.1177/0022034511410699  
  13. AP Putzke, AP Ventura, AM Bailey, C Akture, J Opoku-Ansah, M Celiktas, MS Hwang, DS Darling, IM Coleman, PS Nelson, HM Nguyen, E Corey, M Tewari, C Morrissey, RL Vessella, and BS Knudsen. (2011) Metastatic progression of prostate cancer and E-cadherin. Regulation by Zeb1 and SRC family kinases.  Am. J. Pathol., 179(1): 400-10. PMID: 21703419
  14. Shinya Ohashi, Mitsuteru Natsuizaka, Seiji Naganuma, Shingo Kagawa, Sotai Kimura, Hiroshi Itoh, Ross A. Kalman, Momo Nakagawa, Douglas S. Darling, Devraj Basu, Phyllis A. Gimotty, Andres J. Klein-Szanto, J. Alan Diehl, Meenhard Herlyn, and Hiroshi Nakagawa. (2011) A NOTCH3-Mediated Squamous Cell Differentiation Program Limits Expansion of EMT-Competent Cells That Express the ZEB Transcription Factors. 
    Cancer Research, 71: 6836 - 6847;  DOI:10.1158/0008-5472.CAN-11-0846.
  15. R. Hertzano, R.Elkon, K. Kurima, A. Morrisson, S.L. Chan, M. Sallin, A. Biedlingmaier, D.S. Darling, A.J. Griffith, D.J. Eisenman, S.E. Strome. (2011) Cell type-specific transcriptome analysis reveals a major role for Zeb1 and miR-200b in mouse inner ear morphogenesis.  PLoS Genetics 7(9):e1002309, PMCID: PMC3183091. 
  16. DS Darling, SG Venkatesh, D Goyal and AL Carenbauer (2012). Phosphatidylinositol Bisphosphate Mediated Sorting of Secretory Granule Cargo; Chapter 3 in “Crosstalk and Integration of Membrane Trafficking Pathways,” Dr. Roberto Weigert (Ed.), ISBN: 978-953-51-0515-2, InTech, Available from: http://www.intechopen.com/books/crosstalk-and-integration-of-membrane-trafficking-pathways/phosphatidylinositol-bisphosphate-mediated-sorting-of-secretory-granule-cargo   


Grants (current)

  • 1 P30 ES014443  (PI: Ken Ramos), 06/04/2007   to 03/31/ 2011
    NIH/NIEHS                             Role: Pilot Project Director
    Center for Environmental Genomics and Integrative Biology.
  • R21 EY017869-01  (PI: Darling), 09/30/07 – 8/31/10
    NIH/NEI                     
    Ocular defects caused by TCF8/Zfhx1a/ZEB1 mutations
  • R01 DE019243  (CoPIs: D. Darling + G. Rempala), 09/16/2008 – 5/31/2013
    NIH/NIDCR                      
    Mathematical Model of Parotid Acinar Differentiation
  • R21 DE017378  (PI: C. Binkley),  07/01/2008 – 06/30/10
    NIH/NIDCR
    Oral H. pylori Prevalence in Intellectually/Developmentally Disabled Adults
  • R01DE019243-S1  (CoPIs: D. Darling, G. Rempala), 09/21/2009 – 5/31/2011  
    NIH/NIDCR,    ARRA Supplement                        
    Mathematical Model of Parotid Acinar Differentiation
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