c-kit Differentially Regulates EAE Susceptibility in Male and Female SJL Mice

Project: Research project

Project Details

Description

It is well established that there are sex-based differences in susceptibility to multiple sclerosis.
Not only are women three times as likely to develop MS as men, they are also more likely to
present at a younger age and exhibit a relapsing-remitting course. In contrast, men are generally
diagnosed later in life and most often exhibit a primary- progressive course of disease. The
basis for this sex-determined bias is not fully understood but it is postulated that more robust
immune responsiveness in females, sex-linked genetic effects and influences of sex hormones
on events that regulate disease progression contribute. Certain female hormones expressed at
high levels during pregnancy protect by decreasing inflammatory processes. Later onset of
disease in male patients corresponds with a decline in testosterone with age and treatment with
testosterone in male patients provides therapeutic benefits. In animal models, testosterone is
also protective as shown by increased susceptibility to disease in castrated males and the
decreased disease in testosterone-treated females.
Using a mouse model of multiple sclerosis, our proposed studies will define the cell types that
influence protection from disease in males. We have defined a protein (c-kit) expressed on
immune cells and well as nerve progenitor cells, that when absent, causes males, but not
females, to revert from protection to severe disease. The experiments in this proposal will define
how this molecule exerts its selective protective effects in males.
Remarkably, drugs that modulate the activity of c-kit are already currently in use in other clinical
settings for treatment of certain tumors. In animals these drugs have been shown to exert
neuroprotective effects in models of stroke and CNS injury. Thus, it is important to clarify the
role of these molecules so the possible treatment of MS with such well-studied drugs is not
overlooked. We anticipate that our investigations will provide new insights into the pathologic
mechanisms that underlie both disease in both males and females and lead to improved
therapies.
StatusFinished
Effective start/end date4/1/153/31/18

Funding

  • National Multiple Sclerosis Society (RG 5281-A-3)

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