Source: Interfolio F180

Martin Friedlander

Department of Molecular Medicine


Research Focus

Membrane Protein Topogenesis and Ocular Angiogenesis
Our laboratory is studying (1) the mechanism whereby proteins are asymmetrically integrated into cell membranes and (2) the role of integrins and integrin antagonists in ocular angiogenesis.

Topogenesis of Rhodopsin
Polytopic membrane proteins span the lipid bilayer several times and have hydrophilic domains exposed on alternate sides of the membrane. Opsin (the apoprotein of rhodopsin) is representative of the larger family of G-protein coupled receptors that have seven transmembrane segments (TMS) and eight hydrophilic domains, four of which face the biosynthetic compartment of the cell and four of which are extracellular. By constructing a series of opsin mutants, each containing only a single TMS, we were able to demonstrate that opsin has at least 5 internal signal sequences each of which also expresses a strong or weak stop--transfer sequence. We have recently extended these studies to examine how these topogenic sequences may function to sequentially insert the entire protein into the membrane. In collaboration with Sanford Simon's group at Rockefeller, we have shown that opsin, within a range of nascent peptide lengths, targets and translocates equally efficiently co- and post-translationally and that SRP is required for both co- and post-translational targeting. Futhermore, we have demonstrated that this post-translational targeting and translocation requires nucleotide triphosphates (GTP alone is sufficient to fully restore targeting), but not cytosolic proteins. The addition of ATP was not specifically required and non-hydrolyzable analogs of ATP that blocked 90% of the ATPase activity also had no inhibitory effect on translocation.

Topology of the Na+/Ca++ exchanger from cardiac muscle and photoreceptors
In collaboration with Ken Philipson's group we have been investigating the topology of the cardiac Na+--Ca++ exchanger. Based on hydropathy analysis of the amino acid sequence, the exchanger is proposed to contain 12 hydrophobic segments, the first of which is a cleaved signal sequence. By using a variety of reporter domains (glycosylation sites, epitopes and proteolytic cleavage sites), we have begun to analyze the topology of the exchanger both in vitro and in oocyte expression systems. A full length cDNA clone from photoreceptors has also been obtained and is being similarly analyzed.

The cardiac exchangers have a cleaved amino--terminal signal sequence. Since nearly all other polytopic eucaryotic membrane proteins do not have cleaved signal sequences, we are investigating the putative role of such a sequence in the insertion and targeting of these exchangers. Our results demonstrate that the native, cleaved amino terminal signal sequence is not necessary for insertion of a functional exchanger into the cell membrane. In contrast, the photoreceptor exchanger does not have a cleaved amino terminal signal sequence. If the N-terminal 65 amino acids are deleted, translocation of the N-terminus of the protein is disrupted, but the remainder of the exchanger is integrated into the membrane. Functionally expressed exchanger is being studied using ion exchange assays and two photon scanning laser confocal microscopy of live cell cultures and retinal explants.

Angiogenesis-Dependent Disease
The vast majority of diseases that cause catastrophic loss of vision do so as a result of abnormal blood vessel growth. Pathological retinal or choroidal neovascularization lead to visual loss in diabetic retinopathy (DR) and age related macular degeneration (ARMD), respectively. Similarly, tumors depend on a blood supply for their growth and use these new vessels as an avenue for metastasis. Blood vessels themselves can generate tumors (e.g., hemangiomas) when the growth and organization of vascular endothelial cells is not properly controlled. We are studying each of these areas with the goal of understanding mechanisms of ocular neovascularization in normal and pathological situations. We have used a neonatal mouse retina model to identify regulators of developmental angiogenesis and understand endothelial guidance mechanisms as well as, in a long-standing collaboration with the Cheresh laboratory, evaluate the role of integrins in this process. In other studies, we have shown that bone marrow-derived endothelial precursor cells (EPCs) specifically target retinal astrocytes, incorporate into new vessels and, in a model for retinal degeneration, rescue and stabilize a degenerating retinal vasculature. In collaboration with the Schimmel laboratory we have found that these cells can also be transfected with a plasmid encoding a secreted form of a newly discovered anti-angiogenic, T2 (a fragment of tryptophan tRNA synthetase). Injection of these cells into newborn mouse eyes results in significantly reduced retinal vascularization. Most recently, we have demonstrated that EPCs have a profound neurotrophic effect when injected into eyes of mice with inherited retinal degeneration; not only is the vasculature rescued in these mice, but photoreceptors and visual function are also preserved.

Glioblastoma multiforme is an incurable brain tumor that is usually fatal within one year. We are using gene therapy and a rat model of this disease to study the efficacy of an anti-angiogenic approach in treating these tumors. Hemangiomas are endothelial tumors that proliferate rapidly and later involute spontaneously. We are using DNA microarrays to study changes in gene expression as these tumors progress with the goal of identifying new targets for therapy for these tumors and identifying novel regulators of angiogenesis. In a collaboration with the Nemerow laboratory, we have used pseudotyped adenovirus to selectively target specific cell types in the retina; using the appropriate fiber type we can deliver transgenes to cells, such as photoreceptors, that ordinarily are not targeted by adenovirus.


Nature's Own Medicine for Vision Loss: Inhibitor of Angiogenesis Found by Biologists at The Scripps Research Institute

Vision Researcher Keeps Patients in Focus

Focus on Retinal Eye Diseases

National Eye Institute Funds New Core Center for Vision Research

Stem Cell

An Eye to the Future


M.D. (Medicine), State University of New York Downstate Medical Center, 1983
Ph.D., The University of Chicago, 1976

Professional Experience

1993-1994 Professor, Scripps Research Institute
1994-1996 Assistant Professor, Scripps Research Institute
1997-2005 Associate Professor, Scripps Research Institute
2005-Present Professor, Scripps Research Institute

Awards & Professional Activities

1971 Summa cum Laude in Biologia, Bowdoin College
1971 N.I.H. Predoctoral Fellowship, Developmental Biology Training Program, University of Chicago
1984 Sinsheimer Foundation Scholar, The Rockefeller University
1989 Heed and then Heed-Knapp Fellow in Opthalmology, Jules Stein Eye Institute, UCLA
2000 Royal College of Physicians and Surgeons Lecturer, University of Toronto
2004 Bradley R. Straatsma Lecturer, Jules Stein Eye Institute, UCLA
2006 Inaugural Sayer Lecturer, National Institutes of Health
2006 Alcon Research Institute Annual Award recipient
2006 Recipient of Lions/Sightfirst American Diabetes Association Research Award
2008 Richard C. Troutman, MD, Master Teacher Award in Ophthalmology
2008 Keynote Speaker, Gordon Vision Research Conference
2009 Foundation Fighting Blindness Visionary Award
2009 Friedman Lecturer
2010 Alfred W. Bressler Prize in Vision Science
2013 Keynote Speaker, SUNY Eye Institute Meeting
2013 Werner Strauss Memorial Lecturer, Rosalind Franklin School of Medicine, Chicago IL
2014 Distinguished Lecturer, Northwestern University School of Medicine, Chicago, IL
2015 John Keltner Lectureship in Ophthalmology, UC Davis School of Medicine, Chicago, IL
2015 Visiting Professor, King Khalid Eye Hospital, Riyadh, Saudi Arabia
2015 Joan & Gordon Bergy M.D. Lecture in Vision Science, University of Washington/OHSU, Portland OR
2015 Visiting Adjunct Professor, Department of Ophthalmology, Tokyo Medical University
2016 Honoree, ARVO Foundation Annual Gala Awards Dinner
2018 Joseph M. Bryan Research Lecturer, Duke University
2019 Frontiers in Vision Science Lecturer, Department of Ophthalmology, Luzem, Switzerland  
2020 Symposium Speaker, Swiss Academy of Ophthalmology, Luzern, Switzerland

Selected Publications

Marchetti, V.; Krohne, T. U.; Friedlander, D. F.; Friedlander, Martin Stemming vision loss with stem cells. Journal of Clinical Investigation 2010, 120, 3012-3021.

Weidemann, A.; Krohne, T. U.; Aguilar, E.; Kurihara, Toshihide; Takeda, N.; Dorrell, Michael I.; Simon, M. C.; Haase, V. H.; Friedlander, Martin; Johnson, R. S. Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina. Glia 2010, 58, 1177-1185.

Dorrell, Michael I.; Aguilar, E.; Jacobson, R.; Trauger, S. A.; Friedlander, J.; Siuzdak, Gary; Friedlander, Martin Maintaining retinal astrocytes normalizes revascularization and prevents vascular pathology associated with oxygen-induced retinopathy. Glia 2010, 58, 43-54.

Dorrell, Michael I.; Aguilar, E.; Jacobson, R.; Yanes, O.; Gariano, R.; Heckenlively, J.; Banin, E.; Ramirez, G. A.; Gasmi, M.; Bird, A.; Siuzdak, Gary; Friedlander, Martin Antioxidant or neurotrophic factor treatment preserves function in a mouse model of neovascularization-associated oxidative stress. Journal of Clinical Investigation 2009, 119, 611-623.

Scheppke, L.; Aguilar, E.; Gariano, R. F.; Jacobson, R.; Hood, J.; Doukas, J.; Cao, J.; Noronha, G.; Yee, S.; Weis, S.; Martin, M. B.; Soll, R.; Cheresh, D. A.; Friedlander, Martin Retinal vascular permeability suppression by topical application of a novel VEGFR2/Src kinase inhibitor in mice and rabbits. Journal of Clinical Investigation 2008, 118, 2337-2346.

Dorrell, Michael I.; Aguilar, E.; Scheppke, L.; Barnett, F. H.; Friedlander, Martin Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 2007, 104, 967-972.