CU Boulder researchers tackle HIV-related cognitive decline

Anonymous — Tue, 05 Mar 2024 21:18:40 +0000

CU Boulder researchers tackle HIV-related cognitive decline Anonymous (not verified) Tue, 03/05/2024 - 14:18

Susan Glairon

Assistant Professor Kayla Sprenger

Assistant Professors Kayla Sprenger and Laurel Hind, of CU Boulder’s Department of Chemical and Biological Engineering, are on a collaborative mission to explore solutions for mitigating cognitive decline in individuals living with HIV. This decline can be caused by both the virus itself and the antiretroviral (ARV) drugs used to treat it.

“We're thrilled that this collaborative research is finally happening,” Sprenger said. “It's exciting to work on this together.”

The two secured a $396,000, two-year National Institutes of Health R21 grant to uncover the features of ARVs that impact their interactions with efflux proteins (which remove substances like medications from cells) and lipids in the blood-brain barrier. This knowledge is poised to revolutionize the design of new ARVs, endowing them with an enhanced ability to cross the blood-brain barrier and effectively combat HIV infection in the brain, Sprenger said.

Assistant Professor Laurel Hind

ARVs work by hindering the ability of HIV to replicate. Despite their effectiveness in controlling the virus, 50 to 60 percent of the aging HIV population experiences some form of neurocognitive decline, partly attributed to the treatment, she added.

“ARVs play a crucial role in extending the life expectancy of individuals living with HIV,” Sprenger said. “However, they are accompanied by adverse effects, notably inhibition of host cell proteins that causes neurological impairment. If we can design better ARVs that not only mitigate these side effects but also address neurological complications arising from the presence of HIV itself within the brain, it's like a double whammy of goodness.”

Their research seeks to identify the molecular mechanisms by which ARVs transport across the blood-brain barrier—a critical investigation given the barrier’s role in safeguarding the brain by removing harmful substances, paradoxically including life-saving drugs like ARVs. Beginning with the evaluation of existing ARVs, their approach involves computationally modeling how these drugs diffuse across the blood-brain barrier.

The interdisciplinary project merges Hind’s experimental expertise with Sprenger’s computational approaches. Sprenger has long aspired to conduct computational analyses on how ARVs enter the brain, but has faced challenges in obtaining adequate data. Recognizing this need, Hind provided a model capable of generating experimental data, enabling the collective advance of this research. The experimental data, derived from Hind’s microfluidic blood-brain barrier model, will be crucial in establishing parameters for the development of more biologically-informed computational models.

“Obtaining ‘good data’ has proven challenging due to a scarcity of human data and the limitations inherent in animal models,” Hind said. To address this, the researchers are utilizing a cutting-edge approach, featuring human brain cells within a physiologically-relevant microfluidic model. This approach aims to more accurately replicate the physiological conditions of the blood-brain barrier in their experimental model.

Their ultimate goal is to design new ARVs that can prevent HIV from entering the brain or have an improved ability to diffuse across the blood-brain barrier to stop HIV from replicating within brain-resident cells, all while ensuring that the drug itself doesn’t cause neuronal damage.

Assistant Professors Kayla Sprenger and Laurel Hind are on a collaborative mission to explore solutions for mitigating cognitive decline in individuals living with HIV. This decline can be caused by both the virus itself and the antiretroviral drugs used to treat it.

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CU Boulder researchers tackle HIV-related cognitive decline

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Building the body better: Laurel Hind's immune cell function research receives $1.8 million NIGMS MIRA award

Anonymous — Wed, 30 Nov 2022 15:56:16 +0000

Building the body better: Laurel Hind's immune cell function research receives $1.8 million NIGMS MIRA award Anonymous (not verified) Wed, 11/30/2022 - 08:56

Susan Glairon

When you get an infection, white blood cells called neutrophils are the first to respond, pouring from the bloodstream into infected tissue. Their goal: to kill bacteria.

The problem, says Laurel Hind, assistant professor of Chemical and Biological Engineering and director of the Hind Research Group, is that when neutrophils stay too long, they can damage nearby healthy cells and tissues.

“In the beginning, neutrophils work well because you want all the bacteria or fungus to die,” Hind says. “But when they hang around too long it can lead to chronic inflammation — wounds that don’t heal—or even death from severe sepsis.”

Hind recently received a five-year, $1.8 million National Institute of General Medical Sciences (NIGMS) Maximizing Investigators’ Research Award (MIRA) to study neutrophils and how they interact with other cell types. Her team’s long-term goal: to identify new targets for therapeutic development.

Today infections are primarily treated with broad spectrum antibiotics, but antibiotics are becoming increasingly less effective as pathogens become resistant to them.

“Antimicrobial resistance is going to be one of the worst health crises of our time,” Hind says, adding that simple procedures like joint replacements could become much riskier if infections can’t be treated. “It's called the ‘silent epidemic’ because people don't think about it.”

Hind says a more effective therapy would be twofold: targeting the bacteria with an antibiotic and helping the body’s immune system do a better job. Instead of going after the bacteria, her research focuses on enhancing the body’s immune system, making humans “better fighters.” This strategy is especially important for immunocompromised people who are less able to fight infection.

The Hind Research Group is developing a new approach to treating infections by targeting immune cell function. To do this, researchers first need to understand which signaling molecules, such as proteins, lipids and carbohydrates, lead to differences in neutrophil activity. These signaling molecules bind to specific receptors on the neutrophils’ surface, similar to a lock/key system, leading to signals that "activate" an idle cell so it’s ready to fight.

“Having a new way to target infection will be critical for the continuance of modern medicine,” Hind says. “Hopefully, we are developing answers to the fundamental questions that lead to new therapies.”

Laurel HInd

The engineering difference
For a long time scientists believed neutrophils had simplistic signal mechanisms and functions. Now it’s known that neutrophils are complex and interact with many different cell types.

Most research today involves studying neutrophils in a dish without other cell types present, or using animal models, which have very different immune systems than humans. Hind’s research instead combines human immune cells from healthy donors with live bacteria, which simulates an infection and allows her team to look at interactions between cells.

During a typical immune response, immune cells leave the blood and enter infected tissues. In Hind’s lab, cells flow through model 3D blood vessels surrounded by a tissue microenvironment similar to human tissue. The miniaturized, microfluidic devices, which are built in her lab, mimic what happens in the body during an infection, allowing researchers to study human neutrophil migration and function.

“We're trying to answer very fundamental biological questions about what regulates neutrophils’ behavior,” Hind says. “So when things are going well, what are the things that are going well, and when things go wrong, what types of things can go wrong?”

Because of the award, Hind was able to bring two new graduate students into her lab and to continue funding other graduate students.The team is also starting several new projects which examine cell-cell interactions.

“This award will be hugely beneficial for funding our research, but at a higher level, it means other people are also interested in what we're studying and think this is important,” Hind says. “Asking fundamental questions about the innate immune system has value, and having that recognized is really important.

“It's fascinating to use the tools that we have as engineers to answer the biological questions that people have been looking at for decades with limited success.”

Laurel Hind, assistant professor of chemical and biological engineering, received a five-year, $1.8 million National Institute of General Medical Sciences Maximizing Investigators’ Research Award to study neutrophils, the body's "first responders" to infection.

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CU Boulder researchers tackle HIV-related cognitive decline

Building the body better: Laurel Hind's immune cell function research receives $1.8 million NIGMS MIRA award