This proposal is a mentored training grant that combines research efforts with a didactic plan designed to provide a strong background in immunology, skin physiology/carcinogenesis and the team science approach necessary for the PI's future success as an independent investigator. The PI has a long-standing interest in the inflammatory and immune-related molecular mechanisms of skin disease and the research focus of this proposal investigates the role of Toll-Like Receptor 3 in skin homeostasis, injury and neoplasia. TLR3 is over- expressed within non-melanoma skin cancers (NMSC) and no study to date has examined whether activation of the TLR3 signaling pathway plays a role in protection or is involved in neoplasia initiation and progression. This proposal will use both in vitro and in vivo methodologies to test the overall hypothesis activation of the TLR3 signaling pathway induces injured keratinocytes to acquire cancer stem cell-like properties, which subsequently promotes tumorigenesis.
In Aim 1, we will test the hypothesis that TLR3 signaling promotes changes in keratinocytes consistent with an epithelial-to-mesenchymal transition (EMT).
In Aim 2, we will use both in vitro and in vivo models to test the hypothesis that TLR3 signaling plays a causal role in formation NMSC by UVB. This proposal challenges current research which focuses on pro-inflammatory role of TLR3 and highlights its likely function as an initiator of tumorigenesis. Our proposal is significant in that it will advance the field of skin biology by increasing our understanding of a link between innate immunity and skin tumorigenesis.

Public Health Relevance

The impact of the activation Toll-like Receptor 3 (TLR3) in non-melanoma skin cancer formation is unknown. This innate immune receptor which recognizes double-stranded RNA from viruses and injured host cells to activate the immune system is significantly up-regulated within skin cancers compared to normal skin. A key question to be answered is, 'Is TLR3 signaling promoting cancer formation or is it helping to activate an immune response to fight against it?'

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AR069721-04
Application #
9686531
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Cibotti, Ricardo
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Dermatology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033