Although much progress has been made in understanding multiple sclerosis over the past decades, it is still not clear why, and how, the body begins to attack itself in the disease.
UAB researchers are currently focused on multiple avenues of research, including:
- the JAK/STAT pathway
- molecular control of genes associated with MS susceptibility
- the development and activity of CD4+ T cells
These studies are pointing the way to new targets for MS treatments.
Attacking MS from many angles
Interferon Gamma and JAK-STAT
STAT4
SOCS3
JAK-STAT Pathway
Protein Kinase CK2
TGFBetaRIII
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Interferon Gamma and JAK-STAT
Dr. Chander Raman's lab is testing the hypothesis that increased levels of interferon gamma, working through the JAK-STAT pathway, contributes to the progression and severity of MS. -
STAT4
Dr. Laurie Harrington's lab is focused on STAT4, a protein that is part of the JAK-STAT Pathway. Her lab has shown that lowering STAT4 activity increases resistance to MS in animal models. -
SOCS3
Dr. Etty Benveniste's lab studies SOCS3, a suppressor of the JAK-STAT pathway, in myeloid cells. Her work has shown that SOCS3 decreases inflammation in animal models of MS. -
JAK-STAT Pathway
Dr. Etty Benveniste's lab is studying the therapeutic effect of Jak inhibitors (Jakinibs) in MS. Jakinibs interrupt the JAK-STAT pathway, inhibit the activation of T cells and myeloid cells, and ultimately reduce inflammation in the brain. -
Protein Kinase CK2
Dr. Hongwei Qin is targeting Protein Kinase CK2, which is critical for the development of the pathogenic, IL17 producing T cells in MS. She has shown that inhibiting CK2 activity can reduce neuroinflammation, prevent tissue damage, and promote development of protective regulatory T cells in animal models of MS. -
TGFBetaRIII
Dr. Chander Raman's lab is investigating the role of transforming growth factor beta receptor III (TGFBetaRIII) signals in the development of MS. TGFBetaRIII is involved in determining the fates of CD4+T cells. -
IL10
Dr. Casey Weaver's lab is targeting Interleukin-10 (IL10), an anti-inflammatory signal produced by T-regulatory cells that lowers immune system activity.
Learn more about high-potential research at UAB by clicking the + signs above or reading below.
Inhibiting the JAK/STAT pathway
JAK/STAT is a critical communications route that translates signals from outside a cell into instructions to the cell nucleus, including instructions that increase or decrease immune system activity.
Previous lab research has shown that drugs which inhibit the JAK/STAT pathway may be beneficial in reducing inflammation in the brain. They may offer a new treatment method for MS.
In their labs, Etty (Tika) Benveniste, Ph.D., and Hongwei Qin, Ph.D., are studying the therapeutic effect of JAK/STAT inhibitors, including the components of the immune system involved and how the inhibitors reduce neuroinflammation at a molecular level.
JAK/STAT pathway and Interferon Gamma
One chemical signal that interacts with the JAK/STAT pathway is the cytokine interferon gamma. Chander Raman, Ph.D., is testing the hypothesis that increased levels of interferon gamma, working through the JAK-STAT Pathway, contributes to the progression and severity of MS. In his lab, Raman is identifying the subpopulations of CD4+ and CD8+ T cells with increased interferon gamma signals, and uncovering how this increased signaling contributes to the progression and severity of MS and RA.
Molecular control of MS susceptibility genes
Interleukin-10 is an anti-inflammatory signaling molecule produced by CD4+ T regulatory cells to lower immune system activity. Increasing IL-10 signals in patients with MS could offer a new treatment avenue.
In their labs, Casey Weaver, Ph.D., and Scott Barnum, Ph.D., are uncovering the molecular mechanisms of IL-10 production in MS. They are focusing on the Gfi-1 gene, which is linked to an increased risk for MS. Dr. Weaver’s previous research has found that overactivity of the Gfi-1 gene represses production of IL-10.
Development and activity of CD4+ T cells
CD4+ T cells play a crucial role in fighting off infections. They are also at the heart of the damaging immune response in multiple sclerosis. UAB researchers studying the function of CD4+ T cells are finding new ways to disrupt or reverse the multiple sclerosis disease process. In their labs, they are focusing on several key signaling molecules that affect CD4+ T cells.
STAT4
STAT4 is a protein that is required for the development of Th1 cells from CD4+ T cells. In animal models of multiple sclerosis, lowering STAT4 activity increases resistance to the disease.
In her lab, Laurie Harrington, Ph.D., is working to understand STAT4’s role in the development of MS. She is studying how STAT4 affects the function and accumulation of CD4+ T cells in the central nervous system — in particular the Th17 T cell subtype, which increases inflammation and tissue damage.
Protein Kinase CK2
CK2 is critical for the development of Th17 T cells, which increase inflammation and tissue damage in MS. CK2 also plays a major role in regulating the activity of two critical signaling pathways: JAK/STAT and AKT/PI3K.
By slowing CK2 activity, UAB researchers have demonstrated that they can block the development of Th17 cells and increase development of anti-inflammatory Treg cells, which suppress immune reactions and have a protective effect. This makes CK2 an important new therapeutic target for MS.
In her lab, Hongwei Qin, Ph.D., is focused on documenting CK2’s role in Th17 and Treg cell development, and providing further evidence of its potential as a target for treatment, particularly in patients with Th17 cell-dominated primary or secondary progressive MS.
TGFBRIII
Research by Chander Raman, Ph.D., has discovered a role for transforming growth factor beta receptor III, also known as betaglycan, in the differentiation of CD4+ T cells. In his lab, Dr. Raman is investigating this role, including the question of whether TGFBR3 signals play a role in the development of MS.