Collaborative MS Research Center Award
$742,602; 11/1/09-10/31/14
Principal Investigator
Etty (Tika) Benveniste, PhD
University of Alabama at Birmingham
Birmingham, AL
Co-Investigators
Scott Barnum, PhD
Khurram Bashir, MD, MPH
Michael Brenner, PhD
Rita Cowell, PhD
Patrizia De Sarno, PhD
Candace Floyd, PhD
Richard Jope, PhD
Peter King, MD
Chandar Raman, PhD
John Rinker, II, MD
David Standaert, MD, PhD
Alex Szalai, PhD
University of Alabama at Birmingham
Birmingham, AL
Purpose
Develope and evaluate novel immune system-modulating therapies for MS that can turn off immune attacks and protect nerve tissues.
Summary
Dr. Tika Benveniste is an experienced MS researcher who has assembled an outstanding group of investigators, from both within and outside the field of MS, to develop and evaluate novel approaches to modulate the immune system and protect cells in the brain and spinal cord (“neuroprotection”) in people with MS.
One project will explore the potential of lithium for MS. Lithium has been used for decades to treat psychiatric disease, but it also has the ability to fight inflammation and protect nerve tissues. For this project, Dr. Benveniste is teaming up with MS researchers Drs. Khurram Bashir, Patrizia De Sarno, John Rinker, II, and Chander Raman, and with Dr. Richard Jope, who has an interest in neurodegenerative disorders and psychiatric disorders and expertise in nerve cell pathology.
An enzyme called GSK3 is critical for a variety of cell functions and it also can promote inflammation. Lithium, which inhibits GSK3, has shown promise in mouse models of MS and now the team is analyzing how GSK3 contributes to the immune aspects of the disease. They are also planning a clinical trial of lithium in people with MS.
A second project will investigate the role of proteins, called RNA-binding proteins, in the type of inflammation seen in MS, and determine whether changing the balance of these proteins has therapeutic potential. Teaming up on this project are the experienced MS researchers Drs. Scott Barnum and Tika Benveniste, with Dr. Peter King, who is new to the MS field and brings expertise in the function of RNA-binding proteins in brain disorders.
The team will be using specially engineered mouse models and cells grown in the lab to test their ideas and further tease out which RNA-binding proteins may be potential targets for treatment approaches.
A third project is investigating “C-reactive protein,” or CRP, which in mouse models of MS has been shown to turn down and prevent the immune attack. MS researchers Drs. Alex Szalai and Scott Barnum are teaming up with Dr. Candece Floyd, who is new to MS and brings expertise in spinal cord injury and the role of estrogens (female sex hormones) in possibly protecting nerve tissues against injury.
Blood levels of CRP have been shown to be elevated during MS relapses, and lowered during its treatment, but these investigators believe it may actually be playing a protective role, and without it, MS symptoms would be worse. This team is exploring its interactions with the immune system and also investigating why and how estrogen regulates levels of CRP, for clues to its potential value as a target for future therapies.
The fourth project being undertaken at this Collaborative MS Research Center focuses on immune messengers, called cytokines, and proteins that are capable of altering their activity. Specifically, they are looking at the role of “SOCS” (Suppressors of Cytokine Signaling) proteins, which can reduce inflammatory activity of immune cells and certain brain cells implicated in MS. SOCS proteins appear to do this by inhibiting messages from interferons, which are natural immune messengers, one of which has been developed into an approved treatment for MS.
Teaming up on this project are experienced MS researchers Drs. Benveniste, Bashir, Raman, and Rinker. Collaborating are three researchers who are new to MS: Dr. David Standaert has expertise in the study of movement disorders and genetic aspects that influence disease in animal models; Dr. Michael Brenner is an expert in brain cells called astrocytes and has studied Alexander’s disease; and Dr. Rita Cowell studies the development of the nervous system and autism.
The team will manipulate levels of SOCS in the brain and spinal cord in specific cells and assess the functional impact in mice with MS-like disease and tease out the interplay between the interferons and SOCS proteins. Immune cells will also be extracted from people with MS before and after treatment with interferon beta to determine any differences in SOCS proteins and also to see if there are differences in levels of SOCS proteins between various clinical subtypes of MS and with varying degrees of disability. Ultimately this work will help determine the potential of SOCS proteins as a therapeutic target to treat MS.