Research
The retinal pigment epithelium (RPE) separates photoreceptors from their blood supply in the choroid, and therefore, is responsible for their health. We demonstrated how RPE functions are regulated by interactions with the retina and the choroid. Our goal is to bioengineer a three-dimensional culture model that includes RPE and retinal neurons derived from human stem cells. We will use this platform to screen potential therapeutic agents and determine their mechanism of action.
In mouse models, early transplantation of RPE or retinal progenitors slows retinal degeneration, but later transplantation does not reverse degeneration that has already occurred. We are examining whether the engineered tissue restores vision in late stage disease. In a second approach, we are examining how the process of autophagy may be exploited to reverse degeneration of the RPE.
Current Projects
- We use fetal and stem cell-derived culture models of human retinal pigment epithelium RPE to study mechanisms of retinal degeneration and examine putative therapeutic agents.
- We are investigating the role of autophagy in young and aged RPE, and how changes in autophagy might relate to age-related macular degeneration.
- We use embryonic stem cells to study the interactions of retinal and RPE progenetors with the goal of developing superior engineered tissues for drug testing and transplantation.
- We are investigating how the new Medical School Curriculum impacts the anatomy course. Pedagogical innovation and integration with other courses are being used to deliver a shortened, yet more effective anatomy course.
Research Interests
The retinal pigment epithelium (RPE) plays a central role in retinal physiology by forming the outer blood-retinal barrier and supporting the function of the photoreceptors. Many retinopathies involve a disruption of the epithelium's interactions with the neural retina or its uncontrolled proliferation. Surgical interventions limit the progression of disease, but fail to restore function.
The international community of medical educators struggles with how to decompress an overcrowded curriculum. The questions have become what to teach, when to teach it and how to teach it in less time. The problem is especially acute for anatomy. Even though the classical anatomy course is a large component of medical school, residency programs believe their residents come ill-prepared.
Biomedical Research Photos
The different domains of the RPE plasma membrane are revealed by fluorescent labeling of the microvilli (Na,K-ATPase, red) and basolateral membranes (spectrin, green). In most epithelia, these proteins colocalize in the basolateral membrane, but in RPE most of the ATPase localizes in the microvilli.
In contrast to neurons, epithelial polarity is not inherent in the cell but is induced by the environment. The environment of the RPE changes dramatically as the neural retina and the choriocapillaris differentiate. Just as the polarity of RPE changes during development, the intercellular junctions that bind neighboring RPE cells also mature gradually. These junctions retard diffusion across the RPE through the paracellular spaces. In many epithelia these junctions are relatively leaky, but in the RPE they must be tight to form a blood-retinal barrier. Our studies indicate that this plasticity of the membranes and junctions depends upon interactions with the neural retina.
For reviews see: Wilt SD, Rizzolo LJ: Unique aspects of the blood-brain barrier. In Tight Junctions, Ed. M. Cereijido and J.M. Anderson, CRC Press 2001. Rizzolo LJ: Polarity and the Development of the Outer Blood-Retinal Barrier. Histol. Histopath. 12:1057-1067, 1997.
Two essential features of the RPE are its polarity and barrier properties. The RPE is polarized, because it separates the neural retina from the fenestrated capillaries in the choroid. The apical membrane of RPE interacts with the photoreceptors; the basal membrane interacts with the choroid. Like other epithelia, the apical and basolateral membranes have different protein compositions that enable each to interact with different environments. The barrier properties are regulated by two components. Transepithelial transport through the cells is regulated by plasma membrane pumps and transporters. Passive diffusion through the paracellular spaces is regulated by the strands of tight junctions that encircle each cell. Tight junctions are semi-selective, which means some solutes cross them more readily than others. By regulating both the transcellular and paracellular pathways, the RPE regulates the ionic composition of the subretinal space.
For review see: Wilt SD, Rizzolo LJ: Unique aspects of the blood-brain barrier. In Tight Junctions, Ed. M. Cereijido and J.M. Anderson, CRC Press., 2001. Rizzolo LJ: Polarity and the Development of the Outer Blood-Retinal Barrier. Histol. Histopath. 12:1057-1067, 1997. Rizzolo, L.J. (2007) Development and role of tight junctions in the retinal pigment epithelium, Int. Rev. Cytol. 258:195-234.
RPE tight junctions labeled en face with actin (green) and ZO-1 (red).