Department of Ophthalmology & Gene Therapy Center
University of Massachusetts Medical School
381 Plantation Street
BioTech V, Suite 250
Worcester, MA 01605
Office Phone: 1-508-856-8038
Cells are a steady state open system. The intake of energy has to match the outflow otherwise cells initiate autophagy, the process of self-digestion, to compensate for the shortfall of intake. Persisting energy imbalances for an extended period of time will ultimately lead to cell death. Cell homeostasis is thus tidily linked to cellular metabolism. In neurons, and particularly in photoreceptors (PR) cellular metabolism and the signaling pathways that control it are widely understudied. The assumption is that the constant blood glucose levels readily supply nutrition for neurons, especially since neurons don’t tend to store large quantities of energy. However, fluctuations in nutrient availability can affect cellular responses to short-term stress and lead to cumulative damages over time. These effects can be exacerbated by a genetic predisposition to a particular disease. Thus it is not surprising that diseases that alter body metabolism such as diabetes have now been linked to age-related neurodegeneration diseases such as Alzheimer’s and age-related macular degeneration.
The research focus of my lab is to better understand cellular metabolism in PRs. We strive at understanding how PRs use energy and how the insulin/Akt/mTOR pathway, which controls cellular metabolism, is controlling the flow of energy. Especially, we want to understand how PRs adapt to insults such as a nutrient shortfall and how they adapt to permanent long-term changes of body metabolism such as diabetes. Photoreceptors are specially suited to study metabolism in neurons as they are among the highest energy consuming cells in the human body. Thus they need to adapt fast to any environmental change that alters nutrient availability. For example, in Retinitis Pigmentosa cones appear to die because of a nutrient shortfall caused by the loss of rods. Usually, the disease-causing allele is a rod specific gene. The loss of rods, which outnumber the cones 20:1, causes structural changes to the retina that then cause a nutrient shortfall in cones. Interestingly, cones show signs of metabolic imbalance long before they die. The first signs of metabolic stress are seen in phophorylation changes of mTOR, followed by translational inhibition of some PR specific genes. These observations are not specific to Retinitis Pigmentosa but are also seen in a mouse model of diabetes, which in humans leads to diabetic Retinopathy. However, in this case there is no initial insult in the retina rather the entire body suffers for a metabolic problem. The goal of my lab is to understand how external and/or internal factors, promote and regulate early adaptation of PRs to environmental changes. One particular area of interest is how mTOR selectively inhibit the translation of a small set of PR specific proteins. Understanding what kind of carbohydrate source PRs prefer, how they metabolize it and how the insulin/Akt/mTOR pathway integrates environmental changes, will help to develop preventative treatments.
Punzo C., Kornacker K., Cepko C.L. Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of Retinitis Pigmentosa. (2009) Nature Neuroscience: 12 (1): 44-52.
Punzo C., and Cepko C.L. (2008). Ultrasound-guided in utero injections allow studies of ocular development and function. Developmental Dynamics: 237 (4): 1034-42.
Punzo C., and Cepko C.L. (2007). Cellular responses to photoreceptor death in the rd1 mouse model of retinal degeneration. Invest Ophthalmol Vis Sci.: 48 (2): 849-857.