Itch is a primary symptom of many allergic conditions, and severely affects the quality of life and productivity. Primary sensory neurons residing in the trigeminal ganglia and dorsal root ganglia (DRG) play an essential role in the generation of allergic itch. These neurons detect endogenous itch-inducing molecules (pruritogens) via a group of itch receptors on their peripheral axons in the skin or mucosal membrane tissues, and transmit signals to the spinal cord via their central axons. In contrast to the well-studied histamine pathway, histamine-independent itch pathways in allergic itch remain poorly defined. Previously, we identified several novel itch receptors within a large family of G-protein?coupled receptors called Mrgprs. We found that several Mrgprs recognize distinct pruritogens, and mediate histamine-independent itch. Our latest results indicate that Mrgprs are required for mast cell-mediated allergic itch. This proposal aims to uncover the underlying mechanisms. We will test whether Mrgprs mediate the interaction between mast cells and primary sensory fibers in allergic itch using molecular, genetic and imaging approaches in Aim 1. Furthermore, we will identify the endogenous Mrgpr ligands released by mast cells upon degranulation in Aim 2.
In Aim 3, we seek to translate our discoveries from mice to humans. Human Mrgprs do not form clear orthologous pairs with mouse Mrgprs. Their role in itch is therefore unclear. Based on our preliminary data, we hypothesize that human MrgprX1 mediates neuronal and behavioral response to mast cell-mediated allergy, which will be tested in Aim 3. These studies will reveal the neural basis underlying allergic itch and will have a significant impact on both the study of itch pathogenesis and the clinical treatment of itch.

Public Health Relevance

Despite the clinical importance, the histamine-independent mechanisms of allergic itch remain unknown due to a lack of knowledge about principal pruritogens and itch receptors. This proposal will characterize the role of Mrgprs, a family of histamine-independent itch receptors, in mast cell-mediated allergic itch. These studies will not only advance our understanding of allergic itch at the molecular level, but will also provide a group of new targets for itch management.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI125743-01
Application #
9160145
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Dong, Gang
Project Start
2016-05-12
Project End
2021-04-30
Budget Start
2016-05-12
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Dong, Peter; Guo, Changxiong; Huang, Shengxiang et al. (2017) TRPC3 Is Dispensable for ?-Alanine Triggered Acute Itch. Sci Rep 7:13869
Sun, Shuohao; Xu, Qian; Guo, Changxiong et al. (2017) Leaky Gate Model: Intensity-Dependent Coding of Pain and Itch in the Spinal Cord. Neuron 93:840-853.e5