Research Summary

Multiple Sclerosis (MS) is a common inflammatory disease of the central nervous system. MS has a prominent neurodegenerative component that is most visible in the progressive phase of the disease. The causes of neurodegeneration in MS are poorly understood and are currently not treatable. Our research goal is to better understand the molecular and cellular mechanisms of MS-related neurodegeneration and to translate these insights into therapeutic options.

We are currently studying the impact of genetic MS risk variants that were identified in genome wide association studies, on innate CNS inflammation and neurodegeneration using induced pluripotent stem cell-derived astrocytes, neurons and microglia.

In addition, we are exploring the impact of chronic activation of microglia on tissue injury. For this we are studying autoptic MS tissue and iPSC-derived microglial and perform MS patient imaging with a novel MRI method that detects chronically activated microglia.

My laboratory currently focuses on 2 main areas:

1) Modeling innate inflammation and neuronal degeneration in iPSC-derived CNS cells.

We are examining how genetic risk variants for MS susceptibility or disability may generate a risk state in CNS cells and thereby contribute to neurodegeneration. We generate induced pluripotent stem cells (iPSCs) from skin biopsies obtained from MS patients with risk or protective variants of interest. We then differentiate IPSCs into neurons, astrocytes or microglia to examine their phenotypes. With this approach, we are identifying genetic drivers and mechanisms of MS-specific neurodegeneration. Genetic variants may thus identify patient subgroups vulnerable to specific neurodegenerative mechanisms that can be targeted with tailored treatments.

2) Detecting innate CNS inflammation in MS patients with MRI.

Substantial and presumably long-lasting activation of microglia takes place in MS lesions that cannot be detected with conventional MRI. A striking feature of chronically activated microglia in MS is their high iron content. In collaboration with Dr. Yi Wang (Cornell University, NYC) we are applying a novel MRI technology, quantitative susceptibility mapping (QSM) that is highly sensitive to iron, to MS autopsy tissue and MS patients. We are characterizing iron-induced polarization in microglia in cell culture and in MS autopsy brain tissue using immunohistochemistry and QSM. In MS patients, we are conducting QSM imaging studies to determine the time course and clinical impact of microglial iron deposition. QSM has the potential to become a standard imaging modality used in clinical to detect chronic inflammation in MS patients.