Distinguished Speaker Series | Brian Perkins, Ph.D.

Research

Inherited retinal degenerations (IRDs) are genetic diseases that lead to the progressive loss of photoreceptors and the permanent loss of vision.  Wild-type zebrafish regenerate photoreceptors after acute injury by reprogramming Müller glia into stem-like cells that produce retinal progenitors.  This regenerative process fails to occur in zebrafish models of IRDs.  The goal of my lab is to address the critical unanswered question as to why retinal regeneration fails to occur in zebrafish mutants with photoreceptor degeneraiton and chronic inflammation.  We have found that Notch pathway inhibition can promote photoreceptor regeneration in the zebrafish cep290 and bbs2 models of progressive degeneration and that immunosuppression prevents photoreceptor loss.  These results offer insight into the pathways that promote Müller glia-dependent regeneration and the role of inflammation in photoreceptor degeneration.  Our central hypothesis is that in zebrafish models of retinal degeneration, chronic inflammation results in elevated Notch and NF-kB signaling that restricts the regenerative response to acute injury.  Evidence from the literature and our lab have rigorously demonstrated that Notch signaling in Müller glia differs in response to acute injury or chronic degeneration.  Understanding the link between pro-inflammatory signaling from microglia and Notch signaling in Müller glia has not been previously addressed.  Furthermore, our current understanding of how inflammatory cytokines signal through the NF-kB pathway has only been studied in the context of wild-type animals.  The goal of the lab is to provide critical insight into the relationship between microglia and Müller glia regeneration in chronic disease.  We use state-of-the-art sequencing technologies to identify Müller glia- and microglia-specific changes in gene expression in cep290 and bbs2 models in order to elucidate the relationship between inflammation and regeneration.  We will also identify and test specific ligand-receptor pairs to identify the mechanisms that maintain Notch signaling in the zebrafish degeneration mutants and identify key factors that stimulate NF-kB signaling.  Understanding the mechanisms that underpin retinal regeneration in multiple zebrafish disease models will generate novel hypotheses that can ultimately be translated into humans with retinal degenerative diseases.

Biography

I have been an active participant in vision research for over 25 years and have been continuously funded by the NIH for almost 20 years by R01 and R21 mechanisms.  My laboratory uses zebrafish to investigate photoreceptor regeneration in models of inherited retinal disease. For 20 years I studied
several zebrafish mutants harboring mutations in genes required for cilia function and photoreceptor survival. My independent career started at Texas A&M, where I described early ciliogenesis defects in zebrafish ift mutants. Using a zebrafish model of choroideremia, my group was the first to demonstrate that defects in the RPE initiate and trigger photoreceptor degeneration. We elucidated the requirement for IFT57 within the IFT particle and discovered that retrograde trafficking by dynein-2 motors is essential for photoreceptor survival. After moving to the Cleveland Clinic, my group defined a novel role for the Wrb protein in ribbon synapse function and initiated a long-term interest in zebrafish models of ciliopathies. We described the phenotypes of zebrafish arl13b, ahi1, bbs2, and cep290 mutants and explored genetic interactions between these various genes. Recently, my group has switched our focus to understanding the mechanisms that regulate regeneration in diseased retina. My group discovered that genetic models of  degeneration retain the capacity to regenerate, but require additional suppression of Notch signaling to stimulate Muller cell dedifferentiation and  proliferation.  Since starting my independent lab in 2004, I have trained 8 PhD students and 5 postdoctoral fellows, in addition to over 30 undergraduate students. Trainees from the laboratory have successfully moved into academia, biotech, law, and medicine. I am a strong advocate for trainees to attend scientific meetings to present their work and my goal is to encourage growth in scientific writing and critical thinking skills for trainees at all levels.