Title: Developing a single cell atlas of the median nerve microenvironment in the carpal tunnel
Funder: The Academy of Medical Sciences

Abstract: Carpal tunnel syndrome (CTS) is a very common and disabling condition of the hand caused by compression of the median nerve as it travels through a narrow anatomical tunnel in the wrist. Within the carpal tunnel, the median nerve and the flexor tendons are surrounded by a highly vascular connective tissue known as the sub-synovial connective tissues (SSCT). Fibrosis of the sub-synovial connective tissues are believed to play a central role in the pathogenesis of CTS. We have previously performed the first and only genome-wide association study of CTS, and identified 16 loci in the genome significantly associated with the disease. The genes that mapped to the CTS-associated loci demonstrated strong enrichment for extracellular matrix-associated genes, and we discovered in transcriptomic studies that these genes are highly expressed in the SSCT, suggesting that their aberrant expression is central to CTS pathogenesis. The cellular composition of the SSCT is a poorly understood, and the aim of the proposed research is to perform single-cell RNA sequencing (scSeq) in this tissue to construct a single cell atlas of the cellular microenvironment of the median nerve. I plan to integrate the cell-specific gene expression data with my GWAS data, which will enable mapping of GWAS loci to individual cellular subtypes, thus bestowing disease-specific context to the scSeq data. The ultimate aim of this research is to discover pharmacologically tractable gene or cellular targets in order to prevent or reverse the changes that occur in the SSCT in CTS.

Lay abstract: Carpal tunnel syndrome (CTS) is a very common disease of the hand that is caused by compression of a nerve in the wrist. It affects up to one in ten adults. Patients complain of numbness, tingling, pain in the fingers, and weakness of the thumb - it is therefore a very disabling condition. The main treatment for CTS is surgery, and over 50,000 carpal tunnel operations are performed in the UK each year. While many patients improve following surgery, some patients do not get better, or get recurrent symptoms. There are no effective drug treatments for CTS. We have been studying CTS for the past five years, and have discovered that genes strongly influence the risk of developing CTS. We have found a number of specific genes that play a role in a person’s risk of developing CTS, and these genes are active in the connective tissues that surround the median nerve in the wrist. We now plan to perform an experiment called single cell sequencing in this tissue, which will give us important information about the specific types of cells in which the genes are either over- or under-active. This experiment has never been done in CTS before, and it will help us to identify genes and cell types that can be targeted with drugs. This research will be a big step in providing us with a better understanding of CTS and helping us to develop new treatments, perhaps for the first time helping thousands of people avoid surgery.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL