OU College of Medicine Researcher Earns $1.7 Million Grant to Study Origins of Age-Related Cognitive Impairment

In the process of aging, many older adults bear the heavy burden of dementia and vascular cognitive impairment, conditions that can rob them of quality of life and put them at risk for falls and injuries. To explore a promising premise in aging research — that changes to the brain’s tiniest blood vessels may play an outsized role in cognitive decline — an OU College of Medicine researcher recently received a $1.7 million grant from the National Institutes of Health.

Shannon Conley, Ph.D., an assistant professor in the college’s Department of Cell Biology and a research member of the Oklahoma Center for Geroscience and Healthy Brain Aging, earned the five-year grant, which will allow her to further explore how damaged micro-vessels in the brain may contribute to cognitive decline.

“It has become increasingly evident over the past 10 to 15 years that the smallest blood vessels are important in terms of contributing to disease pathology,” Conley said. “In the brain, this is especially important with aging. Because the brain can’t store any extra oxygen, the loss or damage of even a few tiny blood vessels means there’s not enough oxygen being supplied. In this project, we want to understand what is causing the damage or loss of blood vessels in the brain of an older adult.”

Specifically, Conley is focusing on the relationship between IGF-1, a common growth hormone that promotes blood vessel health, and smooth muscle cells, which surround the outside of blood vessels and help regulate blood flow by contracting and dilating. Researchers know that a person’s IGF-1 levels decline with age and that a deficit of the hormone can lead to defects in blood vessels. However, much less is known about the role of smooth muscle cells in that process.

“The research community has not really looked at the role of IGF-1 deficiency on the smooth muscle cells, specifically in the brain and in the context of aging and age-related cognitive impairment,” Conley said.

For this project, Conley has created an animal model that does not have a receptor for IGF-1 in the smooth muscle cells, resulting in a research model that mimics accelerated aging. Her first aim is to chronicle what happens when the smooth muscle cells can’t respond to IGF-1. Potential effects include damage or loss of blood vessels and impairment of the blood-brain barrier. She will also monitor to see whether the smooth muscle cells become impaired in their ability to contract as they normally do.

“One of the things that is important about smooth muscle cells in the brain is that they contract to protect the small blood vessels from the effects of systemic hypertension,” she said. “If you have systemic high blood pressure, you don’t want the tiny blood vessels in the brain to experience that. They’re very fragile and could have small bleeds or hemorrhages. So we’ll be watching to see if the smooth muscle cells lose their ability to protect the small blood vessels.”

Conley’s study will also seek to determine what is happening on a molecular level when smooth muscle cells cannot respond to IGF-1. “For example, do we see changes in the genes that are associated with cell contraction? Do we see early death of smooth muscle cells?” she said.

Ultimately, one of her goals it to identify targets that might be suitable for a therapeutic intervention. Treating an IGF-1 deficiency isn’t as simple of giving someone a supplement of IGF-1; because it is a growth factor, it could promote abnormal growth in other tissues and cells. However, some of the changes that occur because of IGF-1 deficiency could be a target for future treatments, she said.

Conley’s research is a component of the growing discipline of geroscience research, the study of the biology of aging. Aging itself is one of the biggest risk factors for disease, and many of the cellular mechanisms of aging are common across a wide range of pathologies.

“The things that go wrong in the blood vessel cells in the brain that can lead to dementia are some of the same things that can go wrong in the retina and lead to age-related macular degeneration. And some of those same cellular mechanisms can contribute to the development of Alzheimer’s disease pathologies or Parkinson’s disease pathologies. Among geroscience researchers, there is a lot of interest in what we call the basic cellular mechanisms of aging. We’re not looking specifically at the disease, but how the cells change as we age, and how that increases our risk for a variety of pathologies.”

As people live longer, research like Conley’s is especially important. Medical advancements may be able to keep people alive longer, but many will be diagnosed with conditions that significantly decrease their quality of life.

“As we have longer life spans, it’s really important to identify ways to simultaneously promote increased health spans,” she said. “It’s very challenging when you have loved ones who have severe illness or cognitive impairment, yet they are not dying; they are physically able to keep living. We want to help people stay healthier longer.”

Research reported in this news release is supported by the National Institute on Aging, a component of the National Institutes of Health, under the award number 1R01AG070915-01A1. Federal funds were secured with the help of seed grants from the Presbyterian Health Foundation, the OU College of Medicine Alumni Association, and the Oklahoma Center for the Advancement of Science and Technology.