Chiara Gerhardinger

My training was first as a clinician in diabetes and endocrinology and then as a scientist in molecular biology and cellular physiology. I have been interested in the pathogenesis of diabetic complications since my medical training when I became increasingly aware of the devastating effects of the microvascular complications of diabetes. With this background, I resolved to set my goals on understanding how diabetes induces tissue damage and how this can be prevented.

My primary field of investigation is the pathophysiology of diabetic retinopathy - one of the leading causes of blindness in the adult population of the US. The only therapeutic intervention proven to prevent this complication is the primary treatment of diabetes to achieve near-euglycemia. However, tight metabolic control is not easy to achieve, and intensive insulin therapy is not always practical and free of complications. The therapeutic interventions available at the proliferative stages of the disease are effective in reducing visual loss, but are inherently destructive and not curative. Thus, treatments to preserve visual function in diabetes must target the early events in the pathogenetic process, before the development of vascular lesions. The goal of my research is to understand these events in order to develop new drugs to prevent diabetic retinopathy.

As a postdoctoral fellow, I focused on the molecular mechanisms regulating cell survival and apoptosis of retinal vascular cells in diabetes. I then developed an interest on the effect of diabetes on retinal Muller glial cells, which I pursued as an independent investigator. Müller cells – the main glial cells in the retina – play a key role in retinal glucose metabolism, regulation of retinal blood flow, and maintenance of the blood-retinal barrier. Thus, Müller cells are not only plausible targets of hyperglycemia but potential players in the development of retinal microangiopathy. The first important discovery from this work was the upregulation of GFAP in the Müller cells of human diabetic retinas. This was the first direct evidence that Müller glial cells acquire a reactive phenotype in diabetes– a finding that has since been confirmed by several other investigators both in human and experimental diabetic retinopathy. I further showed that the diabetes-induced reactive phenotype of Müller cells is not the stereotypical response of glial cells to injury but, instead, has a pattern specific to diabetes characterized by the upregulation of acute-phase proteins. The acute phase response is accompanied by the retinal upregulation of the inflammatory cytokine IL-1β, indicating that inflammatory changes may play a role in the development of diabetic retinopathy and pointing to IL-1β as a possible mediator. Another product of this project was the demonstration that gene expression profiling of freshly isolated cells is a feasible ex-vivo approach to identify disease-specific changes in selected populations of retinal cells.

To identify additional molecular pathways that could become therapeutic targets, I have used the same approach to identify all the changes induced by diabetes in retinal vessels –the ultimate and clinically relevant retinal target of diabetes. This work has led to the identification of several processes affected by diabetes in retinal vessels. Two of these pathways are of great interest as potential therapeutic targets to prevent retinopathy. The first process is the development of an acute-phase/inflammatory response, an effect of diabetes common to both retinal glia and vessels. The second process is activation of the TGF-β pathway, an effect of diabetes restricted to the retinal vessels.

My current research goals are:

1. to determine whether inflammatory changes and especially IL-1β have a causal role in the development of retinopathy

2. to determine the role of TGF-β activation as a mediator of retinal vascular damage and remodeling in diabetes. The information generated from these studies will provide critical insights on how diabetes damages the retinal vasculature, setting the stage for the development of innovative approaches to prevent vision loss in diabetes.