Lab web-page: www.umassmed.edu/punzolab
Harvard Medical School, Boston, MA, USA
Postdoctoral fellow, Laboratory of Dr. C.L. Cepko
Biozentrum,University of Basel, Basel, Switzerland
Doctor of Philosophy, Laboratory of Dr. W.J. Gehring
University of Basel, Basel Switzerland
Undergraduate studies, Mentored by Dr. W.J. Gehring
Neuro-Degeneration in the Retina
The vertebrate retina has highly specialized sensory neurons, the photoreceptors (PR), which serve to initiate the process of vision. Cone PRs are responsible for vision during the brighter light intensities of the day and mediate color vision. Rod PRs are 1000x more sensitive to light, and initiate vision in dim light. The light captured by PRs is converted into an electrical signal that is passed on to bipolar cells and then to ganglion cells, the output neurons of the retina, that project to the brain.
Blindness is the inevitable end stage of neuro-degeneration in the retina. The two cell types in the retina that are associated with loss of vision in humans are either the ganglion cells or the PRs. Loss of ganglion cells results in Glaucoma. Loss PRs is associated with a large number of retinal degeneration (RD) diseases. Since PRs account for ~75% of all cells in the retina loss of PRs results always in sever RD.
The research focus of my group is on photoreceptor metabolism and the signaling pathways that regulate photoreceptor metabolism. We study retinal degenerative diseases that affect cone photoreceptors, since cones are essential for color, daylight and high acuity vision in humans. However, because of the peculiar interdependence between rods and cones in humans and mouse we are also interested in rod photoreceptors. In particular, we are interested in how cell metabolism is controlled in both types of photoreceptors of healthy retinas and how cell metabolism adapts during diseases that cause photoreceptor loss. Another area of interest is how photoreceptor metabolism adapts during the process of aging, since aging is known to lead to a host of metabolic changes in the entire body. Additionally, metabolic disease conditions that affect the entire body such as diabetes and only secondarily cause retinal abnormalities such as diabetic retinopathy (DR) are also of interests.
The reason why we are interested in understanding how photoreceptor metabolism is regulated is that photoreceptors are among the highest energy consuming cells in the human body. Two circumstances contribute to the fact that photoreceptors have such a high-energy demand. First, like all neurons photoreceptors need large quantities of ATP in order to re-equilibrate membrane potential. Second, photoreceptors are constantly growing cells yet they do not divide. Photoreceptors need to synthesize every day membranes and proteins they lose due to the shedding of their outer segments. The photoreceptor outer segment is so densely packed to optimize absorption of light photons, that the average lipid content of a photoreceptor is 15% of its cell mass compared to 1% for normal cells and each photoreceptor contains roughly 60pg of protein. Since photoreceptors shed 10% of their OS daily the lipid and protein content that needs to be re-synthesized amounts roughly to that of a cell division per day, suggesting that photoreceptors should have a metabolic profile similar to that of proliferating cells.
One of the disease we are studying in the lab is Retinitis Pigmentosa (RP), which is a family of inherited RD that is untreatable and leads to blindness. The pathology is characterized by an initial loss of night vision due to the loss of rod PR, followed by a progressive loss of cone PRs. In many cases, the disease-causing allele is a gene exclusively expressed in rods; nonetheless, cones die too. There is no known form of RD in humans or mice where rods die, and cones survive. In contrast, mutations in cone-specific genes result only in cone death. Understanding this non-autonomous cone death is the key in designing therapeutic strategies. While the dependence of cones on rods plays an important role in RP it remains a fundamental question of retinal biology.
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