Principal Investigator
Professor of Ophthalmology, Molecular Genetics and Biochemistry
University of Pittsburgh School of Medicine
Publications
Contact Information
UPMC Vision Institute
UPMC Mercy Pavilion
1622 Locust Street
Pittsburgh, PA 15219
O: 412-647-6319
F: 412-647-5880
kinchingtonp@upmc.edu
Research Focus
We work mostly on the herpesvirus Varicella zoster virus (VZV) and how it switches between these states. VZV causes chickenpox and the painful elderly disease Shingles, aka Herpes Zoster. Zoster on the head threatens the eye by clouding the cornea, damaging or even destroying the retina, or causing neurological diseases ranging from serious pain and unwanted eye movements and complete loss of corneal sensation.
We do research in VZV to answer three big overarching questions.
First, why does a VZV infection cause so much pain? Pain is a frequent consequence of Zoster in humans and for some, the pain is debilitating or extremely difficult to treat. To study VZV pain, we have developed model systems that allow us to probe not only the mechanisms underlying VZV induced pain, but also to test new potential treatments of pain.
Second, how does the virus switch between latent and active states? VZV hides in sensory neurons of ganglia for decades and may reawaken to cause Shingles. We have new platforms of cultured human neurons that model the latency reactivation switch, and we are genetically probing the functions of VZV RNAs made during latency. Do they help the virus maintain the silent latent stage, or do they play roles in the switch to reactivation and shingles?
Third, why the live virus VZV vaccine is attenuated for growth in humans? There are good vaccines for VZV. The Chickenpox vaccine is a live attenuated virus that grows poorly in human skin and has been given to tens of millions of people. However, it is a complex genetic mixture, and occasionally causes disease that can be serious. A better varicella vaccine might be one in which there are defined mutations that affect growth in human tissues. We therefore are examining a few of the vaccine associated mutations in models of human skin and nervous tissues.
It is our overall goal to find answers to these big questions and apply them to reduce or even prevent the ocular diseases associated with this Herpesvirus.
Grants
NIH:- NIAID R01 AI158510, Kinchington (PI) "VZV vaccine attenuation and the DNA Damage response” 07/01/22-06/30/27 Major goals are: (1) to determine if the high frequency and near fixed VZV vaccine virus mutations found in the ORF62 gene (encoding the key VZV regulatory IE62 protein) are responsible to the virus attenuation seen for the vaccine in human skin models. (2) to determine if the same mutations alter the ability of the ORF62 protein to regulate the pro-viral DNA damage response to facilitate infection in skin, and if this is mediated through the human differentiating skin specific factor cytokeratin15; (3) To determine if these and other vaccine specific mutations in the IE62 regulatory protein underlie to poor reactivation of VZV from latency, using model reactivatable latent states with cultured neuron platforms.
NIH: - NIAID R01 AI151290, Kinchington (co-PI with Verjans G) " Role of VZV latency transcript (VLT) and ORF63 in latency and reactivation” 11-15-2020 to 10-30-2025. The work in this research seeks to characterize the role and expression of the RNAs made from the “VLT” locus that is antisense to ORF61, that is transcribed during VZV latency in human ganglia. Aim 1 seeks to identify neuronal subtypes that host a VZV latent state in which the VLT transcript is expressed. Aim 2 seeks to genetically dissect the VLT locus through the development and evaluation of VZV recombinants. Aim 3 seeks to address the chromatin changes that occur around the VLT locus as the latent state transitions to reactivation.
NEI P30 EY08098 (04/01/1988-03/31/29) "Core Grant for Vision Research" The Core Grant provides support for the five centralized research modules. Dr Kinchington is now Director of the Virus Production and Protein Modulation Core module
T32 EY 0172171) Interdisciplinary Visual Science (IVS) Training Program (06/01/2024-2029: currently in year 16). Dr Kinchington is contact PI and Codirector with Marlene Behrmann. The T32 supports a training program to train the next generation of Vision Scientists