Members of the Department of Pharmacology have broad interests in understanding the biological mechanisms that keep us functioning, what changes cause disease and ways we can target those changes to restore healthy function. We are engaged in ground-break research in the vasculature, cancers, and other areas.
Our department is dedicated to educational opportunities, offering undergraduate and graduate courses, a Minor in Pharmacology, a Master’s in Pharmacology, Medical School curriculum, and research opportunities for both CMB and NGP graduate students.
Cerebrovascular:
We explore the mechanisms of cerebral blood flow, how it is controlled to meet the ever- changing demands of active neurons (neurovascular coupling - NVC) and how these mechanisms are disrupted in small vessel disease (SVD) – a major cause of stroke and dementia. Our research has shown that brain capillaries act as a neural activity-sensing network to activate blood flow to active neurons. We use mouse models of SVD to discover early defects that result in impairments. We are working to create a systems-level view of physiological signaling in the brain microcirculation, test the concept that gradual degradation of this sensory web, and the progressive dysfunction that contributes to SVD in the brain to target these deficits and improve cerebrovascular function.
Our researchers have found a novel mechanism of cerebral blood flow regulation involving TRPV1 channels in the arterial smooth muscle in non-brain arteries of the head. Activation of TRPV1 channels in non-brain arteries can boost blood flow in the brain. Our hypothesis is that TRPV1 channel activation represents a long-term neuro-protective mechanism against cerebral blood flow deficits and impaired neurovascular coupling the precedes cognitive decline and dementia. Importantly, we have found that a long-term dietary addition of the TRPV1 activator capsaicin slowed the decline of recognition memory in Alzheimer’s model mice. Ongoing research continues to examine the impact of dietary capsaicin on cerebral blood flow and the pathological changes in brain structure.
Additionally, we are investigating how cerebral artery diameter is regulated, targeting cell signaling pathways contributing to enhanced cerebral artery constriction following cerebral aneurysm rupture and subarachnoid hemorrhage (SAH). Aneurysmal SAH occurs in ~ 30,000 people in the US each year with high rates of morbidity and mortality. Current treatments are very limited and do little to improve patient outcome. Our research has identified a dual-system molecular module centered on activation of the epidermal growth factor receptor (EGFR) in both arteriolar smooth muscle and the astrocyte endfeet that encase these arterioles within the brain parenchyma. EGFR activation through two distinct pathways represents a significant breakthrough toward new therapeutic interventions.
Urinary Bladder Control:
Understanding the basic physiology, in particular, the ion channels that regulate the function of the bladder smooth muscle and how this contributes to the excitability, contractility, and coordination of voiding. By identifying and characterizing these channels, we aim to uncover mechanisms that maintain normal bladder function and contribute to dysfunction in disease. Our research aims to bridge the gap between basic bladder physiology and the neural circuits that govern urinary voiding behavior.
Cancer Research:
The thyroid produces hormones that regulate the body’s metabolic rate, growth and development, and help maintain health. Thyroid hormone receptor beta (TRb) is a recognized tumor suppressor in numerous solid cancers. The molecular signaling of TRb has been elucidated in several cancer types through re-expression models. Our researchers are investigating selective activation of TRb to amplify the effects of therapeutic agents to induce tumor suppression and enhance the effectiveness of anticancer agents.
Epigenetic signaling is the process that controls gene activity without altering the underlying DNA sequence. These signals involve modifications to DNA and associated proteins, such as histones, which affect how genes are expressed. We are working to understand how epigenetic signaling regulates gene expression, and how alterations in these pathways are involved in disease development, particularly cancer and infectious disease. We are investigating the molecular mechanisms driving the recognition of histone post-translational modifications to identify new therapeutic strategies.
The extracellular matrix (ECM) is a network of molecules, found outside of cells that provides structural and biochemical support to surrounding cells and tissues, influencing various cell processes. Cells interpret the composition of their ECM and respond to the extrinsic forces by modifying their behavior, remodeling the ECM itself, and exerting counter-tension. In normal cells, this ‘mechanoreciprocity’ is in controlled equilibrium and is important for tissue homeostasis. Tumor cells exploit changes to facilitate local growth, invasion and spread. We are investigating the way cells interpret their ECM and the signaling pathways which control cell shape and movement, and particularly how changes in the extracellular microenvironment regulate the progression, invasion, and dissemination of cancer.
Mark T. Nelson, Ph.D.
University Distinguished Professor and Chair