Multiple Sclerosis (MS) is an autoimmune disorder characterized by inflammation, demyelination, and neurodegeneration. Despite wide symptomatic variability, gray matter (GM) atrophy has consistently emerged as a strong indicator of clinical disability. In fact, evidence suggests progressive loss of GM correlates with disability and cognitive dysfunction better than many other magnetic resonance imaging biomarkers of MS, including enhancing lesions and lesion burden. While 40-70% of patients experience cognitive decline over the course of disease, there is no treatment on the market that can halt the progression of GM atrophy or cognitive decline. Current treatment options are primarily designed to reduce inflammation and have had only modest success at slowing GM atrophy in MS. Treatment with the sex hormone estriol has been shown to reduce relapses and preserve GM in both MS and in experimental autoimmune encephalomyelitis (EAE), its most commonly used mouse model. Recently, in a clinical trial with female MS patients, estriol treatment was shown to reduce GM atrophy and improve performance in cognitive testing. The mechanisms underlying the neuroprotective effects of estriol remain unclear. Understanding how estriol is working to preserve GM tissue may lead to the development of better neuroprotective therapies for patients with MS and potentially other neurodegenerative conditions. Our preliminary data suggest that estriol treatment in EAE reduces GM atrophy and neuronal loss in the cerebral cortex and prevents axonal transection in the spinal cord. Further, we have found that axonal transection in the spinal cord is correlated with GM volume almost exclusively in the motor and sensory motor cortices. In this proposal, I will utilize the EAE mouse model to 1) identify regions where estriol treatment preserves GM volume and what changes in pathology are associated with GM preservation, 2) characterize the effect of estriol on oxidative stress in mitochondria, and 3) identify genes differentially expressed in cortical neurons from estriol-treated animals. This project will provide invaluable information about how estriol provides neuroprotection in GM and will highlight potential targets for future neuroprotective therapies.

Public Health Relevance

Preventing gray matter (GM) atrophy and cognitive decline has been an important goal in Multiple Sclerosis (MS) treatment. While estriol has been shown to be neuroprotective and to prevent disability in MS, very little is known about the mechanisms underlying this effect. This project will investigate how estriol preserves GM, how it effects mitochondrial (dys)function, and how it alters gene expression in cortical neurons to provide neuroprotection in the most commonly used mouse model of MS, experimental autoimmune encephalomyelitis (EAE).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS105387-03
Application #
9991944
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Utz, Ursula
Project Start
2018-09-01
Project End
2021-05-31
Budget Start
2020-09-01
Budget End
2021-05-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095