The Mendelowitz lab is focused on how the autonomic nervous system, and particularly specific populations of neurons in the brainstem, control heart rate, airway resistance, and other essential cardiorespiratory functions. In addition to understanding the role of these neurons in normal physiology, we also seek to determine how these neurons and pathways are altered to initiate and/or sustain cardiorespiratory diseases, particularly in the prevalent cardiovascular diseases obstructive sleep apnea and heart failure. Our overarching goal is to identify novel targets of opportunity for treating these diseases.
We strive to test if targeted manipulation of the receptors and neurotransmitters in the cardiorespiratory network can restore autonomic balance, improve treatment of cardiorespiratory diseases and prevent adverse cardiovascular events. My lab tests these important clinically relevant hypotheses by quantifying changes both in-vivo and in-vitro. Our approaches include telemetry recordings of blood pressure, heart rate and heart rate variability while selectively altering the activity of specific neuronal targets using viral mediated expression of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) that elicit long duration changes in the activity of targeted neurons. To test our hypotheses in-vitro we use optogenetic approaches, as promoter driven expression of channelrhodopsin that permits selective photoexcitation of specific neurons and/or pathways while quantifying, using patch clamp electrophysiology, post-synaptic responses. One of our more recent approaches uses CHO cells, which we have engineered to serve as biosensor sniffer cells, to directly assess endogenous neurotransmitter release and concentrations at cardiorespiratory targets.
Our work has bench-to-bedside translational potential, and has provided the foundation for clinical studies (ClinicalTrials.gov NCT03148899 and NCT02564068) with our collaborator, Dr. Vivek Jain, Director, Sleep Clinic, Medical Faculty Associates, George Washington University.