Douglas Dean, Ph.D.

Research Faculty

CONTACT INFORMATION:

301 E. Muhammad Ali Boulevard,
Louisville KY 40202
Telephone: 502-852-5466 Fax: 502-852-8550

EDUCATION / TRAINING

Kansas University Medical School, PhD, 1983 – Biochemistry

Baylor College of Medicine – Post-Doctoral 1983-1986 – Cell Biology

Salk Institute – Post-Doctoral – 1986-1988 – Cell Biology

 

PERSONAL STATEMENT

We have a long-standing interest in pathways regulated by the retinoblastoma protein in cell proliferation and cancer progression.  Interestingly, these same pathways control generation and maintenance of cancer stem cells as well as expansion and differentiation of adult progenitor cells, a more recent focus of the laboratory. In the studies proposed here, we build on our recent publications transplanting and characterizing the differentiation of photoreceptor precursors in the retina of a pig RHO P23H model of RP.  During the course of these studies, we noted and characterized the effect of replacing rods on restoration of cone function in this model.  Because such loss of cone function is key in diminished functional central vision as RP progresses, we have examined the mechanism of the rod protection of cone function.  These findings form the basis for the proposal.


ACADEMIC POSITIONS AND HONORS

10/05 – present            Robert W. and Gretchen Rounsavall Professor of Ocular Oncology

Department of Ophthalmology

James Graham Brown Cancer Center

Birth Defects Center

University of Louisville School of Medicine

Louisville, KY

 

6/6/98 – 10/05             Head, Molecular Oncology Program

Professor of Medicine and Cell Biology and Physiology

Washington University School of Medicine

St. Louis, MO

 

HONORS

Newmark Award for Biological Research

University of Kansas

 

Spirit of Health Award

American Cancer Society

 

NIH SERVICE

Past member of Molecular Biology Study Section and Pathobiochemistry Study Section

CONTRIBUTION TO SCIENCE

Rb represses transcription and regulates cell proliferation by epigenetic modification.  In earlier studies, the laboratory provided the first evidence that the Rb family interacts with epigenetic modifiers such as HDAC and polycomb proteins to stably regulate expression of target genes and control cell proliferation.

 

Rb has expanding roles in development and signaling.  The first studies of the Rb family suggested that the proteins interacted with E2F to regulate entry of cells into the cell cycle.  We demonstrated that Rb also regulates entry of cells into M phase and it targets a number of other pathways critical for signaling and normal development.

 

Cell-cell contacts regulate cell programming.  We demonstrated that that cell-cell contacts and hypoxia regulate Hippo and Wnt signaling to control cell programming.  Activation of these pathways is sufficient for conversion of cancer cells into cancer stem cells/tumor initiating cells and for dedifferentiation of RPE.


ZEB1, EMT and RPE.  ZEB1 is a prototypical transcriptional regulator of EMT long linked to tumor metastasis.  However, there is emerging evidence that early EMT is key in establishing tumors as well as playing a deciding role in early vs. late metastatic potential.  We show that ZEB1 induction is required for lung adenocarcinoma initiation, and it interacts with the Rb family pathway to trigger sarcoma initiation. Additionally, we showed that Zeb1 induction drives dedifferentiating EMT in a cell-cell contact dependent fashion in RPE.

  • Liu Y, Xin Y, Fei Y, Wang W, Lu Q, Kaplan HJ and Dean DC. Taz-Tead1 Links Cell-Cell Contact to Zeb1 Expression, Proliferation and Dedifferentiation in Retinal Pigment Epithelial Cells.  Invest Ophthal Vis Sci 2010 Jul;51(7):3372-8. doi: 10.1167/iovs.09-4321. Epub 2010 Mar 5.
  • Liu Y, Ye F, Li Q,  Tamiya S, Darling DS, Lu Q, Kaplan HJ, and Dean DC. 2009.  Zinc Finger E-Box Binding Homeodomain 1 (Zeb1) Represses Pigment Cell Specification Factor, Mitf, and Regulates Epithelial-Mesenchymal Transition of Retinal Pigment Epithelial Cells. Ophthalmol. Vis. Sci. 50: 5080-5088.  PMID: 19515996
  • Zhang P, Wei Y, Wang L, Debeb BG, Yuan Y, Zhang J, Yuan J, Wang M, Chen D, Sun Y, Woodward WA, Liu Y, Dean DC, Liang H, Hu Y, Ang KK, Hung MC, Chen J, Ma L. 2014. ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1. Nature Cell Biol. 16:864-75. PMID:25086746
  • Liu Y, Lu X, Huang L, Wang W, Jiang G, Dean KC, Clem B, Telang S, Jenson AB, Cuatrecasas M, Chesney J, Darling DS, Postigo A, Douglas C. Dean DC.    Different Thresholds of ZEB1 are Required for Ras-Mediated Tumor Initiation and Metastasis. Nature Commun 5:5660. PMID:25434817.

Glycolytic dependence and rod and cone precursors in development and transplantation.  We have followed the differentiation potential of rod and cone progenitors in the developing pig and have shown that precursors with rod differentiation capacity differentiate before cells with cone differentiation capacity.  And, populations of rod precursors at different developmental states display distinct capacities for rod and cone generation for transplantation.  We are examining differences in metabolism in rod and cone precursors and linking differences to functional interplay between these photoreceptor subtypes.

 

Complete List of Published Work in My Bibliography:

http://www.ncbi.nlm.nih.gov/myncbi/collections/bibliography/47098521/

Grants

 

Current

CA149438.  NIH.  Activation of cyclin dependent kinases by fructose-2,6 bisphosphate. (Jason Chesney, PI; Douglas C. Dean, Co-I). 6/1/11 – 5/31/16.

 

CA150764.  NIH.  EMT transcription factors and cancer.  (Levi Beverly PI, Douglas C. Dean Co-I).  8/1/15-7/31-20.

 

EY024110.  NIH. Hypoxia-induced reprogramming to RPE stem cells.  (Douglas C. Dean PI), 6/1/14 – 5/31/18.

 

MR130345. DoD.  Stem Cells and Vision Restoration Following Traumatic Injury.  (Douglas C. Dean PI). 9/1/14 – 8/31/17.

 

Research to Prevent Blindness Stein Innovation Award (Douglas C. Dean, PI). 7/1/15 – 6/31/17.

 

Pending

EY026060.  Biochemical and metabolic analysis of cone outer segment generation (Douglas C. Dean, PI). Analysis of differences in rod and cone metabolism during the functional interplay between these photoreceptor subtypes.

 

CA177623.  NIH. Role for ZEB1 in K-ras-initiated lung cancer (Douglas C. Dean, PI).  This proposal is to examine the role of the EMT transcription factor ZEB1 in a mouse lung cancer model.  No overlap with the current proposal.

 

EY026158. NIH. Cone rescue in retinitis pigmentosa (Henry J. Kaplan and Douglas C. Dean dual-PIs).  This proposal aims to evaluate physiological effect of transplanting rods precursors into a model of pig retinitis pigmentosa.

 

Terminated in the past three years

Source Type Role Title Year:
NEI R21 PI Zeb1 and epithelial-mesenchymal balance in the eye. 10-12
NCI R01 PI Molecular Regulation of Epithelial-Mesenchymal Transitions 09-12
NEI R01 Co-I MerTK regulation of the PTTG and RPE phagocytosis 08-14
NIH P20 Co-I Molecular Determinants of Developmental Defects 12-14
NEI R21 Co-I 14-3-3o and epithelial differentiation in the eye 11-13
DOD Co-I Novel use of clinical drugs to prevent major eye injury 10-14
RPB PI RPB Lew Wasserman Award 11-12