Hearing Loss
Certain types of chemotherapeutic drugs are known to cause some degree of hearing loss. This is an unfortunate and inevitable side effect of life-saving therapy. We would like to change that. Our lab has used a genetic mouse model to show that removal of a cell surface protein known as S1P2 results in degeneration of the inner ear and profound deafness. Conversely, we also have shown that activation of this protein has the opposite effect: it protects cells that are similar to inner ear cells and makes them more resistant to death due to chemotherapy. We have identified a compound that can activate S1P2 and are currently developing it into a drug that may prevent hearing loss due to chemotherapy or other damaging processes.
How does this fit into the core focus of the lab? S1P2 is normally activated by a specific lipid known as sphingosine 1-phosphate (S1P). Our background research into this very special lipid has given us the insight to conceptualize this novel approach to preventing deafness.
Dementia
Dementia is an increasing problem in our rapidly aging population but currently has no effective treatment options. We are investigating the potential involvement of a particular class of lipids, sphingolipids, in the development of the two most common forms of dementia: Alzheimer’s disease and vascular dementia. We have found that one particular sphingolipid (there are over 600 known forms) is specifically reduced in patients with vascular dementia, but not in patients with Alzheimer’s disease. This finding will allow us to better understand the differences between vascular dementia and Alzheimer’s disease. Furthermore, we find that the reduction in this particular sphingolipid likely causes an increase in chronic brain inflammation, which leads to a worsening of dementia. Our current work involves understanding how this process effects the relationship between the brain and its vasculature (the blood-brain barrier).
Drug Development
In collaboration with the Drug Discovery and Optimization Program, we have recently begun unbiased drug screening efforts. We are developing high-content imaging assays to evaluate the activation of inflammatory signaling pathways. These assays are being used in a medium-to-high throughput screening platform to identify novel anti-inflammatory compounds that are present in natural products such medicinal herbs.
Inflammation
Pyroptosis: note the balloon-like swelling of the cells.
We are interested in how inflammatory processes are regulated by lipids, particularly those processes that cause diseases of the nervous system, such as pain and dementia. One recent observation identified DHA, the major component of fish oil, as a regulator of an inflammatory process known as pyroptosis. This syggests that tight regulation of DHA metabolism is important to control chronic inflammation in the brain.
Please see our related manuscript here: Metabolism of docosahexaenoic acid (DHA) induces pyroptosis in BV-2 microglial cells
Cancer
Cancer is a highly complex collection of diseases that are influenced by countless signaling systems. Many studies have demonstrated that sphingosine 1-phosphate (S1P) generally promotes tumor growth and drives cancer development. We are interested in how S1P signaling contributes to epithelial-mesenchymal transition (EMT), which is a process by which cancer cells become reprogrammed into a metastatic state. We recently found that S1P stimulates SNAI2 (also known as “slug”), which is one of the “on” switches for the EMT program. This means that S1P incubates cancer cells in an environment that stimulates tumors to become metastatic.
Please see the full study here: Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells.