Sean Marrelli, Ph.D.
Ph.D.: Baylor College of Medicine, 1998
- Control of Cerebral Blood Flow:
Vascular endothelium, calcium regulation, ion channels, KCa channels, TRP channels
- Therapeutic Hypothermia:
Thermoregulation, temperature-sensitive ion channels, TRPV1 & TRPM8 channels, stroke
Awards and Honors
- Fulbright & Jaworski L.L.P. Faculty Excellence Award for Teaching and Evaluation (2010)
- Annual Cardiovascular Specialty Award (2010) - Society of Critical Care Medicine
- Lyndon Baines Johnson (LBJ) Research Award for 2006 - The American Heart Association, Texas Affiliate
- Servier Young Investigator Award (2001)
- Arnold O. Beckman Academic Achievement Award (1998)
Description of Research
There are two major research areas of my laboratory.
- The most long-standing area of research involves the study of the vascular endothelium in the control of cerebral arteries and arterioles in both normal and pathological conditions, such as ischemia/reperfusion (stroke). In particular, my laboratory studies the role of transient receptor potential (TRP) ion channels in the regulation of endothelial calcium concentration. Through activation of certain TRP channels, the endothelial calcium concentration is increased to trigger activation of calcium-activated potassium channels (KCa). Activation of these channels produces endothelial cell hyperpolarization and subsequent artery dilation. We are studying the mechanism of this process of vasodilation in the cerebral circulation at the cellular, intact artery, and whole organism level.
These studies have employed multiple methodologies including measurement of vessel diameter in isolated pressurized/perfused arteries and arterioles, selective measurement of endothelial Ca2+ concentration or membrane potential by optical dyes or biosensors, measurement of smooth muscle membrane potential by sharp electrode, and measurement of message and protein by standard molecular techniques. We also examine K+ channel and TRP channel function at the cellular level in freshly isolated smooth muscle and endothelial cells using patch-clamp techniques. Most recently, we have begun studies at the whole organism level through the use of a variety of transgenic and knockout mouse models.
- A more recent area of research involves the study of therapeutic hypothermia in the application of stroke. Induction of mild hypothermia (32-34 °C) is effective in promoting greater recovery following cardiac arrest. However, there are currently several limitations to the methods of producing hypothermia that limit application of this promising treatment strategy to stroke patients. We are investigating novel methods of producing hypothermia through the pharmacological targeting of temperature-sensitive ion channels within the thermoregulatory system. In particular, we are studying TRPV1 (also known as the capsaicin receptor) and TRPM8 channels (also known as the cold receptor or the menthol receptor). We have successfully used capsaicinoids (spicy component in chili peppers) to produce sustained and reversible hypothermia for the treatment of ischemic stroke.
The therapeutic hypothermia studies are broken into two primary areas of study. In one area, we are focused on the mechanism of shivering and pharmacological control of shivering. Since shivering is the primary clinical complication with therapeutic hypothermia protocols, broader application of this treatment option will require new treatment strategies for the control of shivering in the conscious subject. In these studies, we measure shivering (by EMG), heart rate (ECG), and thermogenesis (core temperature and indirect calorimetry) in response to cold challenge following selective TRP channel activation/inhibition or in specific TRP channel knockout mice. In a second area, we are focused on the application of these strategies to the treatment of stroke. To maximize the potential clinical application of these studies, we have designed treatment protocols that are compatible with the conscious and freely moving subject. These studies employ a transient ischemia/reperfusion model, osmotic delivery of TRP channel modulators, and histological and functional analysis of neuroprotection.
- Kochukov MY, Balasubramanian A, Noel RC, Marrelli SP. Role of TRPC1 and TRPC3 channels in contraction and relaxation of mouse thoracic aorta. J Vasc Res. 50(1), 11-20 (2013).
- Senadheera S, Kim Y, Grayson TH, Toemoe S, Kochukov MY, Abramowitz J, Housley GD, Bertrand RL, Chadha PS, Bertrand PP, Murphy TV, Tare M, Birnbaumer L, Marrelli SP, Sandow SL. Transient receptor potential canonical type 3 channels facilitate endothelium-derived hyperpolarization-mediated resistance artery vasodilator activity. Cardiovasc Res. 95(4), 439-47 (2012).
- Lloyd EE, Crossland RF, Phillips SC, Marrelli SP, Reddy AK, Taffet GE, Hartley CJ, Bryan RM Jr. Disruption of K(2P)6.1 produces vascular dysfunction and hypertension in mice. Hypertension. 58(4), 672-8 (2011).
- Noorani MM, Noel RC, Marrelli SP. Upregulated TRPC3 and downregulated TRPC1 channel expression during hypertension is associated with increased vascular contractility in rat. Front Physiol. 2:42 (2011).
- Bryan RM Jr, Marrelli SP. Endothelium-dependent hyperpolarization: out of the dish and into the brain. J Cereb Blood Flow Metab. 31(5), 1173-4 (2011).
- Namiranian K, Lloyd EE, Crossland RF, Marrelli SP, Taffet GE, Reddy AK, Hartley CJ, Bryan RM Jr. Cerebrovascular responses in mice deficient in the potassium channel, TREK-1. Am J Physiology Regul Integr Comp Physiol. 299(2), R461-9 (2010).
- Lloyd EE, Marrelli SP, Namiranian K, Bryan RM Jr. Characterization of TWIK-2, a two-pore domain K+ channel, cloned from the rat middle cerebral artery. Exp Biol Med. 234(12), 1493-502 (2009).
- Chen J, Crossland RF, Noorani MZ, Marrelli SP. Inhibition of TRPC1/TRPC3 by PKG contributes to NO-mediated vasorelaxation. Am J Physiology. (In Press)
- Lloyd EE, Marrelli SP, Bryan RM Jr. cGMP does not activate two-pore domain K+ channels in cerebrovascular smooth muscle. Am J Physiology. 296(6), H1774-80 (2009).
- Shafi NI, Andresen J, Marrelli SP, Bryan RM Jr. Erythropoietin potentiates EDHF-mediated dilations in rat middle cerebral arteries. Journal of Neurotrauma. 25(3), 257-65 (2008).
- Smith PD, Brett SE, Luykenaar KD, Sandow SL, Marrelli SP, Vigmond EJ, Welsh DG. Kir channels function as electrical amplifiers in rat vascular smooth muscle. Journal of Physiology. 586(4), 1147-60 (2008).
- Sokoya EM, Burns AR, Marrelli SP, Chen J. Myoendothelial gap junction frequency does not account for sex differences in EDHF responses in rat MCA. Microvascular Research. 74(1), 39-44 (2007).
- Marrelli SP, O'Neil RG, Bryan RM Jr. PLA2 and TRPV4 channels regulate endothelial calcium in cerebral arteries. Am J. Physiology: Heart Circ. Physiol. 2007; H1390-H1397.
- Bryan RM, You J, Phillips SC, Andresen JJ, Lloyd EE, Rogers PA, Dryer SE, Marrelli SP. Evidence for Two-Pore Domain Potassium Channels in Rat Cerebral Arteries. Am J. Physiology: Heart Circ. Physiol. 2006; H770-H780.
- Marrelli SP: Endothelial Ca2+ and endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilation. Chapter 37 in Microvascular Research: Biology and Pathology. 2006; 239-245.
- Bryan Jr RM, You J, Golding EM, Marrelli, SP: Endothelium-derived hyperpolarizing factor. A cousin to nitric oxide and prostacyclin. Anesthesiology 102(6): 1261-1277, 2005.
- Marrelli SP, Eckmann MS, Hunte MS: Role of endothelial intermediate conductance KCa channels in cerebral EDHF-mediated dilations. American Journal of Physiology. 285, H1590-H1599, 2003.
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