Prajna Dhar - Supplement Project
Project Title
Understanding the role of cholesterol and the female sex hormone, estrogen, on the mechanical properties of model myelin membranes
Principal Investigator
Prajna Dhar, Professor, Chemical and Petroleum Engineering
Project Summary
Women are three times more likely than men to be diagnosed with multiple sclerosis (MS), an autoimmune disease, where the body’s immune system attacks and damages the myelin sheath that insulates nerve cells. While early in the disease, damaged myelin is regenerated or remyelinated, with aging and/or with multiple attacks, the body loses its ability to efficiently repair this myelin sheath. Further, hormone-related physiological events, such as the post-partum period, and onset of menopause, often also show periods of exacerbations of MS. These observations point to a potential role of the female sex-hormone, estrogen, in MS progression.
Currently there are no FDA approved therapeutic interventions to reverse myelin damage in MS patients, partly because of our limited understanding of the remyelination process. Recent biochemical studies have presented conclusive evidence that lipid metabolism pathways, and the lipid and protein composition of the myelin sheath, play important roles in MS. However, currently very little is understood about which lipids modulate the structural integrity of the membrane.
The overall objective of this project is to understand how the altered lipidome that results during demyelination impacts the structural integrity of the myelin sheath. Preliminary data from our labs conclusively demonstrate that remyelinated myelin lipid extracts, isolated from a mouse model of demyelination, are significantly less stiff, compared to healthy controls. Further, we find that altered cholesterol levels (but not altered phospholipid levels) play a dominant role in lowering the membrane stiffness. Using novel biophysical techniques, this proposal will test the overarching hypothesis that estrogen contributes to the structural integrity of the myelin sheath, by controlling the lipid composition of the myelin sheath during myelin repair and by altering lipid packing. The specific aims are to determine how 1) cholesterol’s interaction with major and minor lipid classes found in the myelin sheath helps maintain the structural integrity of the myelin membrane 2) estrogen induced changes in the lipid profile lead to alteration of the membrane mechanical properties of the myelin sheath. The innovation in this proposal is the application of novel biophysical techniques to characterize the stiffness and fluidity of the myelin sheath during remyelination and correlate these observations with biochemical changes in the lipidome. Successful outcomes of this project will be significant as our work will address a knowledge gap regarding how estrogen and different lipid classes contribute to maintaining the structural integrity of the myelin during remyelination. This knowledge is necessary for identifying new therapeutic targets to reverse demyelination.