Targeting Chemerin Receptor CMKLR1 in Multiple Sclerosis

Principal Investigator: ZABEL, BRIAN A
Program: MSRP
Proposal Number: MS100248
Award Number: W81XWH-11-1-0512
Funding Mechanism: Idea Award
Partnering Awards:
Award Amount: $610,032.64


Multiple sclerosis (MS) is a debilitating medical condition in which the body's immune system turns on itself and attacks the myelin insulation that coats nerve fibers in the brain. When the myelin sheath is damaged, the transmission of electrical signals through nerves is impaired, leading to the clinical symptoms of MS. In order to destroy myelin, the immune cells that coordinate the attack must migrate into the brain. Immune cell migration is controlled by small protein "chemoattractants," and in MS chemoattractants play a key role in recruiting destructive immune cells into the brain. In fact, a few chemoattractants (and chemoattractant receptors, which are expressed on the surface of immune cells) have already been identified that contribute to immune cell migration into the brain.

Our work focuses on a chemoattractant receptor called CMKLR1, which is located on the surface of specific immune cells. Mice that lack the CMKLR1 receptor develop significantly less severe "EAE," an MS-like disease. In addition, CMKLR1-deficient mice have fewer inflammatory cells in the brain and spinal cord. Chemerin, a chemoattractant that binds to CMKLR1 and triggers cell migration, is found at high levels in the spinal cords of mice with EAE. Together, these results demonstrate that CMKLR1 contributes to destruction of central nervous system (CNS) tissue in a mouse model of MS and suggest that therapies that target CMKLR1 or chemerin may be beneficial to MS patients.

The goal of this proposal is to identify novel drugs that target the CMKLR1 receptor and then test their ability to reduce disease in a mouse model of MS. Drugs that bind to CMKLR1 and block migration of cells to chemerin may prevent immune cell entry into the brain and thus reduce damage to the myelin sheath. We propose to screen a large library of potential drugs to identify candidates that specifically inhibit CMKLR1. In preliminary studies, we have already identified a candidate drug that specifically blocks cell migration to chemerin. We propose to determine how much of the drug we can safely administer to mice, and then test it in the EAE model of MS. We will also investigate how our candidate drug (as well as other CMKLR1-selective drugs) affects immune cell migration. If we are able to prevent immune cells from entering the CNS, we would likely prevent or reduce the severity of MS.

The discovery that CMKLR1-deficient mice develop less severe EAE disease originated in our laboratory (published just seven months ago), and the approach to recapitulate this observation with drugs that target CMKLR1 is entirely novel and innovative. Furthermore, there are no publications describing CMKLR1-selective drugs. Thus, our preliminary work and our screen to identify additional CMKLR1-specific drugs are pioneering. Finally, evaluating our candidate drugs for effects on cell migration using microfluidics chambers is an innovative approach using conditions that mimic blood flow in vessels. Using these innovative approaches, our goal is to identify drugs that prevent the migration of specific immune cells into the brain and reduce the severity of demyelinating disease in a mouse model of MS. Thus, our proposal may offer new opportunities in the clinic to treat patients with MS.