Therapeutic Value or Harm of Neuregulin 1 in Demyelinating Disorders
Abstract
It is still not clear whether the primary process in multiple sclerosis is degenerative, immunological, or both. In fact, both demyelination/remyelination of axons and micogolial immune activation are important observations both in patients with MS and in animal models. Neuregulin 1 is both a membrane bound and secreted growth and differentiation factor that regulates glial development and survival, synaptogenesis, axoglial interactions, and recently microglial activation. Given these diverse actions, NRG1 could be a potential therapeutic target for CNS demyelinating disorders. However, it is unclear whether NRG1 would actually be helpful or harmful as a therapeutic treatment because of its diverse effects. In this proposal we will test a novel, targeted fusion protein that specifically disrupts neuregulin1 signaling in an inducible transgenic mouse model to determine the effects of NRG1 signaling in two demyelinating animal models. The therapeutic efficacy of this entirely humanized antagonist is achieved by combining NRG1 s own heparinbinding domain with a NRG1 receptor decoy so tha tit targets the same that NRG1 does. Transgene induction at different stages of both the cuprizone and EAE models will be used to determine both the effects of NRG1 on disease progression as well as on demyelination and remyelination on tissues. Whether or not NRG1 signaling is beneficial or harmful in these models, the availability of both NRG1 agonists and antagonists could rapidly lead to biologically driven, targeted therapeutics in patients with multiple sclerosis and other demyelinating disorders.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2012
- Accession Number
- ADA575576
Entities
People
- Jeffery Loeb
Organizations
- Wayne State University