Experimental autoimmune encephalomyelitis (EAE) is a CD4 T cell-dependent model for the human disease multiple sclerosis (MS). In these diseases, a complex immune response is orchestrated toward central nervous system (CNS) myelin. Ultimately, the cascade of inflammatory events culminates in myelin and neuronal damage, mediated in large part by phagocytic immune cells such as infiltrating macrophages and activated microglia. The molecular regulation that governs inflammatory responses by these innate cell subsets remains unclear. In preliminary studies, we have discovered that the Transient Receptor Potential (TRP) cation channel, TRPV4 is expressed by microglial cells and functions to propagate effector inflammatory responses during EAE. These data have led us to hypothesize that expression of TRPV4 by innate immune cells, including circulating monocytes and microglia, contributes to the pathogenesis of MS and can be modulated to reduce the severity of neuro-inflammation. We will employ three complementary aims to explore this hypothesis. First, we will determine the cellular basis of TRPV4-mediated neuro-immune interactions in the CNS using both radiation bone marrow chimeras and a new murine reagent we have designed in which TRPV4 is conditionally expressed in vivo. Second, we will determine the therapeutic effect of TRPV4 inhibition during EAE. Third, we will examine human tissue and material from an extensive bio-repository to assess the expression of TRPV4 in immune cells and MS lesions. This highly translational study will establish the cellular mechanism of TRPV4- dependent immune activation during EAE, the potential for pharmacologic modulation of neuro-inflammation via TRPV4, and the pattern of TRPV4 expression in patients with MS. Thus, this study engenders a unique opportunity to identify a molecular target for the rational design of treatment for neuro-inflammatory diseases such as MS.
In this proposal, we will explore the mechanisms by which the calcium channel TRPV4 regulates neuro-inflammation in multiple sclerosis (MS). Using an animal model of MS, we will define the relevant cellular expression of TRPV4 as well as the effect of inhibiting TRPV4 function during disease. Further, we will examine immune cells and nervous system tissue from MS patients for TRPV4 expression to gain further understanding of optimal treatment strategies targeting this channel.
