William “Tré” Mills III, PhD, mentored by Ukpong Eyo, PhD, recently received a K99/R00 grant award from the NIH. The award will fund his project, “The Role of Microglia-Pericyte Signaling in Maintaining Basal Capillary Tone in Health and Alzheimer’s Disease,” for two years in the Eyo Lab at UVA, then provide additional funding to kickstart his independent research career.
Broadly, Mills seeks to understand how microglia, the primary immune cells in the human nervous system, regulate blood flow through the brain’s smallest blood vessels. In studies of the human genome, many of the genes that indicate risk for Alzheimer’s Disease (AD) are found in microglia, suggesting that these cells play a role in the disease. One of the key indicators of AD is reduce blood flow through the brain, the earliest sign a person is developing the condition. As the disease progresses, blood flow to the brain can drop by over 25%, effectively starving neural cells. Microglia, as immune cells, are responsible for controlling brain inflammation, which in turn affects cerebral blood flow. Taken together, these factors all suggest microglia could be valuable drug targets for improving AD treatments.
An influential work in the Alzheimer’s field, known as the Rotterdam Study, reviewed 11,475 patient records and found that early and prolonged treatment with non-steroidal anti-inflammatory drugs protected against AD. These drugs are common, including pain medications like aspirin and ibuprofen, but the reason they help Alzheimer’s patients is unclear. They are also imperfect treatments. “These drugs have severe gastrointestinal toxicity, so if we can learn what specifically we want to target, we can think about a more precise method to make a better, safer drug,” explained Mills. Through advanced genetic and imaging methods, Mills will visualize the flow of blood through mice and measure how age and pain medication affect it. If pain medication offers no benefit beyond genetic perturbation, then a more precise target can be inferred, thereby aiding future therapeutic development.
A former member of the cardiovascular training program at the CVRC, Mills attributes part of his success to the grant brewing sessions and mentorship he was able to access through the program. The K99 will assist his further development by providing access to training and materials that will make him more competitive for independent research faculty positions in the future. “I’ll be able to do experiments that we haven’t been able to do before,” Mills said. “My dream is to someday make cost-effective therapeutics for Alzheimer’s Disease.”