The adult mammalian central nervous system contains a population of immature, undifferentiated, multipotent cells, neural stem cells (NSCs) that may be called upon for repair in neurodegenerative and demyelinating diseases. NSCs may, in turn, give rise to oligodendrocyte progenitor cells (OPCs) and other myelinating cells, as well as neural and glial precursors. The capacity of NSCs to repair damage in the adult has been demonstrated in several experimental systems. However, in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) remyelination and neuro-regeneration do not occur to a sufficient extent. During the previous funding period we have examined the effects of inflammation on the multipotentiality of neural stem/progenitor cells in vivo and in vitro. We found that NSCs proliferate, start to differentiate, and migrate out of the subventricular zone during the acute phase of the disease. But as the disease progresses proliferation of the stem cells subsides. Furthermore, we have observed that during chronic EAE, microglia remain activated in the absence of inflammatory infiltrates. This situation is reminiscent of the chronic phase of multiple sclerosis, where neuro-degeneration and loss of brain parenchyma occur in the absence of gadolinium enhancing lesions on MRI. We will examine the hypothesis that chronically activated microglia are responsible, at least in part for the dysfunction in stem cell function. We will address this hypothesis in the following aims.
Aim 1. Differential interaction of acutely versus chronically activated microglia with neural progenitor cells.
Aim 2. How do NSCs modulate microglial activation in the SVZ.
Aim 3. We will examine if reversal of chronic microglia activation will restore normal NSC functionality. These investigations will have an impact on our understanding of the pathogenesis of neuro-degeneration in multiple sclerosis and provide a model that may be used to target treatments for chronic disease.

Public Health Relevance

Despite recent advances in the diagnosis and treatment of multiple sclerosis (MS) we still lack a consensus regarding the etiology, pathogenesis and the mechanisms of disease progression. This proposal will address the hypothesis that the innate immune system (through persistent activation of microglia) may play a role in the chronic dysfunction of neural stem/progenitor cells. The findings will have impact on understanding the pathogenesis of disease progression in MS and may provide a model for testing new therapies for preventing neuro-degeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043496-12
Application #
8486361
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Esch, Thomas R
Project Start
1999-04-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
12
Fiscal Year
2013
Total Cost
$369,667
Indirect Cost
$134,667
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Imitola, Jaime; Cote, Daniel; Rasmussen, Stine et al. (2011) Multimodal coherent anti-Stokes Raman scattering microscopy reveals microglia-associated myelin and axonal dysfunction in multiple sclerosis-like lesions in mice. J Biomed Opt 16:021109
Rasmussen, Stine; Imitola, Jaime; Ayuso-Sacido, Angel et al. (2011) Reversible neural stem cell niche dysfunction in a model of multiple sclerosis. Ann Neurol 69:878-91
Elyaman, Wassim; Bradshaw, Elizabeth M; Uyttenhove, Catherine et al. (2009) IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A 106:12885-90
Kivisakk, Pia; Imitola, Jaime; Rasmussen, Stine et al. (2009) Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann Neurol 65:457-69
Wang, Yue; Imitola, Jaime; Rasmussen, Stine et al. (2008) Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis. Ann Neurol 64:417-27
Pluchino, Stefano; Muzio, Luca; Imitola, Jaime et al. (2008) Persistent inflammation alters the function of the endogenous brain stem cell compartment. Brain 131:2564-78
Imitola, Jaime; Khoury, Samia J (2008) Neural stem cells and the future treatment of neurological diseases: raising the standard. Methods Mol Biol 438:9-16
Elyaman, Wassim; Kivisakk, Pia; Reddy, Jay et al. (2008) Distinct functions of autoreactive memory and effector CD4+ T cells in experimental autoimmune encephalomyelitis. Am J Pathol 173:411-22
Chitnis, Tanuja; Imitola, Jaime; Wang, Yue et al. (2007) Elevated neuronal expression of CD200 protects Wlds mice from inflammation-mediated neurodegeneration. Am J Pathol 170:1695-712
Zhu, Bing; Bando, Yoshio; Xiao, Sheng et al. (2007) CD11b+Ly-6C(hi) suppressive monocytes in experimental autoimmune encephalomyelitis. J Immunol 179:5228-37

Showing the most recent 10 out of 18 publications