The University of Texas Health Science Center at Houston
McGovern Medical School
Department of Neurology
A longstanding central theme of research in the Marrelli Lab involves the mechanisms of cerebrovascular function, in both healthy and pathological conditions. There are multiple ongoing projects in the lab, of which three are summarized below.
In project 1, we seek to define how Piezo1 (a mechanosensitive ion channel) contributes to blood flow regulation in the brain. Our data indicates Piezo1 expression and function within brain endothelial cells. We have further shown that selective genetic deletion of Piezo1 in endothelium results in reduced cerebral blood flow (CBF) and that pharmacological activation of Piezo1 promotes increased CBF. We are currently exploring how loss of endothelial Piezo1 function contributes to decreased brain perfusion in mouse models of aging and amyloidosis. In addition, we are determining if selective augmentation of endothelial Piezo1 function can improve brain perfusion in these same models. In project 2, we are investigating the role of von Willebrand factor (VWF) in cerebrovascular remodeling. VWF is produced in endothelial cells and can be released from Weibel-Palade bodies into the blood as large multimers following endothelial cell activation. Release of VWF also occurs constitutively, delivering smaller multimers into the plasma and subendothelial space. While VWF is best known for its contribution to healthy hemostasis, recent data suggest that VWF may also function within the vascular wall (i.e. “intramural VWF”) to modify smooth muscle function. Our data show the presence of VWF within the vascular wall and in tight association with smooth muscle cells in both human and mouse brain vessels in aging, stroke, and amyloid-dependent pathology. We are currently examining the mechanisms by which intramural VWF promotes vascular remodeling and impaired vasomotor function of the leptomeningeal arteries/arterioles in human and mouse brain and determining if reducing intramural VWF can protect those vessels from pathological remodeling and impaired function. In project 3, we are using ‘non-pungent’ TRPV1 channel agonists to promote therapeutic hypothermia following ischemic stroke. Delivery of these agonists promotes mild hypothermia (core body temp 33-35 °C) and thereby lessens stroke injury and improves functional recovery.
Experimental approaches used in the Marrelli Lab include, laser speckle contrast imaging (measurement of dynamic CBF responses, recruitment of collateral vessels), microCT imaging (in vivo and ex vivo; 3D quantitative measurement of brain vasculature, brain pathology, parenchymal clearance), MRI (measurement of white matter injury, absolute CBF), two-photon imaging (pial vascular function, perivascular clearance), wireless body temperature measurement, histology/immunofluorescence, AAV-mediated gene deletion, RNAseq and scRNAseq, and behavior testing. We use a variety of transgenic mouse models, such as inducible Piezo1 KO, inducible Piezo1 GOF, VWF KO, Tg2576 mice, TgSwDI mice, inducible TRPV1 KO, and a variety of reporter mice. Lastly, we use a variety of surgical models to induce ischemic stroke or deliver experimental agents to the brain.
Education & Training
Ph.D. - Baylor College of Medicine - 1998