Ferguson Lab

Thomas Ferguson, PhD, Professor, Ophthalmology and Visual Sciences

Research 

The laboratory studies the role of autophagy in the pathogenesis of eye diseases such as age-related macular degeneration (AMD) and other retinal degenerative diseases. We are pursuing this by creating mice in which basal autophagy is deleted in specific cell types in the eye. Recently we found that a link between the autophagy machinery, phagocytosis of photoreceptor outer segments, and the regeneration of chromophore by the visual cycle in the retinal pigment epithelium (RPE). Our results showed that the autophagy protein LC3 associates with single membrane phagosomes containing engulfed POS in an Atg5-dependent manner that also requires Beclin1 but not Ulk1, Atg13, or Fip200 of the autophagy pre-initiation complex. This process termed LC3 associated phagocytosis (LAP) is necessary for optimal vision. Thus, in contrast to conventional autophagy, our studies suggest that a non-canonical form of autophagy functions to support chromophore regeneration through the efficient processing of outer segments by the RPE.

Our studies have also shown that autophagy is critical to function and long term survival of rod and cone photoreceptors. Studying autophagy in photoreceptors has given us new insights into the metabolism, function, and stress responses of these cells that are critical to vision. Cones are particularly dependent on autophagy as they utilize this process for their continued function in intense bright light and activate the pathway in response to light stress and systemic nutrient starvation.

Although we are members of the vision science community at Washington University we are also part of the Immunology group. Our studies have concentrated on the molecular basis of immune tolerance and how apoptotic cells tolerize the immune response. Our studies try to understand the molecular basis of this type of immune regulation using biochemistry and gene targeting technology. Currently we are studying what it is about apoptosis, per se, that reprograms dendritic cells away from their ability to activate immunity to potent inducers of immune tolerance. We have determined that during apoptosis the activation of caspases and the destruction of the mitochondria are critical in the ability of apoptotic cells to induce immune tolerance. A key feature is that the production of ROS (reactive oxygen species) during apoptosis oxidizes (and inactivates) the damage associated molecule HMGB1 high mobility group box 1 protein). When HMGB1 is not oxidized, apoptotic cells can stimulate the immune response. Thus one role of the apoptotic process is the inactivation of damage associated signals to prevent aberrant immune responses.

Publications

View Thomas Ferguson’s NCBI publications on PubMed»

Recent Original Reports:

  1. Kim JY, Zhao H, Martinez J, Doggett TA, Kolesnikov AV, Tang PH, Ablonczy Z, Chan CC, Zhou Z, Green DR, Ferguson TA. Noncanonical autophagy promotes the visual cycle. Cell 154:365-376. 2013. PMC3744125
  2. Zhou Z, Doggett TA, Sene A, Apte RS, Ferguson TA. Autophagy supports survival and phototransduction protein levels in rod photoreceptors. Cell Death Differ. 22:488-98, 2015. PMC4326583
  3. Doyle SL, López FJ, Celkova L, Brennan K, Mulfaul K, Ozaki E, Kenna PF, Kurali E, Hudson N, Doggett T, Ferguson TA, Humphries P, Adamson P, Campbell M. IL-18 Immunotherapy for Neovascular AMD: Tolerability and Efficacy in Nonhuman Primates. Invest Ophthalmol Vis Sci. 56:5424-30, 2015. PMID: 26284546
  4. Zhou Z, Vinberg F, Schottler F, Doggett TA, Kefalov VJ, Ferguson TA. Autophagy Supports Color Vision. Autophagy, 11:1821-32. 2015 PMC4824586.
  5. Yin XT, Keadle TL, Hard J, Herndon J, Potter CA, Del Rosso CR, Ferguson TA, Stuart PM. Impaired Fas-Fas Ligand Interactions Result in Greater Recurrent Herpetic Stromal Keratitis in Mice. J Immunol Res. 2015; PMC4609448
  6. Ferguson TA, Laurie GW. Introduction to Autophagy in the Eye (or “What’s Eatin’ You?”). Exp Eye Res. 2016 PMC4777279
  7. Santeford A, Wiley LA, Park S, Bamba S, Nakamura R, Gdoura A, Ferguson TA, Rao PK, Guan JL, Saitoh T, Akira S, Xavier R, Virgin HW, Apte RS. Impaired Autophagy in Macrophages Promotes Inflammatory Eye Disease. Autophagy Epub July 2016. PMID: 27463423

Book Chapters

  1. Ferguson TA and Niederkorn JA: Anterior Chamber Associated Immune Deviation. IN: Ocular Infections and Immunity. JS Pepose, GN Holland, and KR Wilhelmus, eds. Mosby-Year Book, Inc., Philadelphia, PA 1995
  2. Ferguson TA and Van Gelder, RV: Immune Function and Ocular Disease. IN: Samter’s Immunologic Diseases, Sixth edition. KF Austin, MM Frank, JP Atkinson, and H Cantor, eds. Lippincott, Williams & Wilkins, Baltimore, MD. 2001