Principal Investigator: Cynthia Leifer
Contact Information: E-mail: cal59@cornell.edu - Phone: 607-253-4258
Sponsor: NIH-NIAID
Grant Number: 3 R01 AI076588-01A2S1
Title: ARRA: Toll Like Receptor 9: Trafficking and Signaling
Annual Direct Cost: $67,556
Project Period: 09/17/09-08/31/10
DESCRIPTION (provided by applicant): Rapid and accurate recognition of invading pathogens is critical for survival from infectious diseases. Toll-like receptors (TLRs) are a family of innate receptors poised to rapidly recognize components of infectious organisms. Originally it was thought that TLR also provided accurate discrimination between infectious organisms and the host. However, four different TLRs recognize nucleic acid ligands that are shared between the pathogen and the host. Recognition of shared ligands contributes to autoimmune disease and raises questions about the safety of using such ligands for immunotherapuetic approaches. Our overall goal is to elucidate the molecular mechanisms regulating TLR signaling, using TLR9 as a model. The studies proposed in this supplement will accelerate the pace of discovery, add a new dimension of novelty and increase the overall impact of our original application while staying within the original hypothesis and aims. These studies are complementary to the parent proposal, use the same experimental techniques and will support our original hypothesis. Supplemental funds are requested to create a new job for a postdoctoral associate who has recently been awarded a PhD. An additional associate will allow (1) a more rapid completion of the original proposed studies, and (2) intense study on our novel and high impact observation. During the progress of our current RO1 research we have made a very exciting and provocative new finding. In addition to the previously described cleavage product of TLR9 to generate an active form, we have observed a second cleavage product, as demonstrated by immunoprecipitation and mass spectrometry analysis. This second cleavage event is regulated differently and likely terminates TLR9 signaling. Given the novelty of this finding, and the potential for regulating response to TLR9 agonists, it is of great importance to continue this work. Rapid and regulated cleavage of TLR9 likely plays a fundamental role in allowing accurate discrimination of host and foreign ligands by generating an acitve form in the correct geographical location within the cells, while similarly generating a signal terminating form to prevent response to self ligand and excessive signaling.