Dianne Perez, PhD, Staff Researcher in Cardiovascular and Metabolic Sciences at Cleveland Clinic, knew a few things from an early age: she would work in her hometown of Cleveland and pursue chemistry as many of her family members before her. After graduating top of her chemistry class at the College of Wooster, the first time there for a woman, and pursuing a chemistry graduate degree at the California Institute of Technology, her premonitions became a reality when she joined Cleveland Clinic as a post-doctoral fellow in 1990.
In her 30 years with Cleveland Clinic, Dr. Perez has made some astounding discoveries. Leveraging her chemistry and molecular biology backgrounds, Dr. Perez focused her science on alpha-1 adrenergic receptors – the receptors that bind adrenaline in the body to regulate its “fight or flight” response. Thought for a long time only clinically-relevant in cardiovascular function, these receptors were viewed in a new light with Dr. Perez’s ensuing research.
Following the initial cloning of the receptors and some early publications in the space, Dr. Perez and her team conducted mutagenesis to change some of the amino acids found in these receptors, allowing them a clearer picture of how the hormones of epinephrine and norepinephrine bind in the receptor pocket. For this greater understanding of structure-function, Dr. Perez credits her chemistry background.
After their structure-function studies, Dr. Perez and her team moved to research these receptors in unique transgenic mouse models that they designed. These animal models overexpressed the alpha-1 adrenergic receptor subtypes in a systemic way – allowing expression in all natural tissues of the body. The receptors contained mutations which allowed them to be continuously activated even if epinephrine or norepinephrine were not present, increasing the possibility of identifying previously undetected sites of activity. Its expression in all organs and continuous activation is what led to Dr. Perez’s crowning discovery: the receptor’s prominent role in brain neurotransmission and cognition.
To fully examine their presence in the brain, the team tagged these receptors with a green fluorescent protein. In a map of the brain, one particular alpha-1 subtype (alpha-1A) was highly expressed in the cognitive centers of the hippocampus, cerebral cortex, and amygdala, leading the team to wonder if the stimulatory effect of an agonist of this receptor could enhance cognition. Through trial and error, the team gained a greater understanding of just how specific a drug would need to be for these alpha-1 adrenergic receptors and designed the first iteration of six potential drug compounds.
In the past two years, Dr. Perez identified her most significant research advancement as the design and completion of a 10-month dosing study of their lead compound in an Alzheimer’s mouse model with human mutations. Significant study results were seen through qualitative cognitive tests (Barnes maze, fear-conditioning, etc.) and higher stimulation in the neurons of the brain’s memory centers (known as long-term potentiation).
More recently, Dr. Perez and her lab received a new RO1 grant from the National Institute on Aging (NIA) to conduct a second in-vivo study of their lead compound. In this study, they will examine dose efficacy with three different doses tested against placebo for three months. This should help Dr. Perez and her team gain insight into the drug’s impact on memory improvement over a shortened time period. Dosing in these animals started November 1, 2020, and Dr. Perez hopes for results by the end of March 2021. Positive results could support a longer-term focus on this lead compound toward clinical development.
Other future plans include ramping up drug derivations in an attempt to identify other compounds that might better penetrate the brain for increased potency and targeted in vivo studies to analyze potential side effects. Through her near 30 years of research, Dr. Perez has made great headway in the space of neurodegenerative disease drug development. With much still on the horizon, we celebrate her work with 2020’s Outstanding Innovation in Therapeutics and Diagnostics award.