A5012351376- Pulmonary Hypertension Research and Treatments
- Angiogenesis and VEGF in Cancer
- Cellular Mechanics and Interactions
- 3D Printing in Biomedical Research
- Neonatal Respiratory Health Research
- Axon Guidance and Neuronal Signaling
- Hippo pathway signaling and YAP/TAZ
- Cell Adhesion Molecules Research
- Cancer, Hypoxia, and Metabolism
- Congenital heart defects research
- Cancer Cells and Metastasis
- Periodontal Regeneration and Treatments
- Tissue Engineering and Regenerative Medicine
- Microtubule and mitosis dynamics
- Electrospun Nanofibers in Biomedical Applications
- Eicosanoids and Hypertension Pharmacology
- Ion Channels and Receptors
- Protein Kinase Regulation and GTPase Signaling
- Apelin-related biomedical research
- Lipid metabolism and disorders
- Signaling Pathways in Disease
- Mechanisms of cancer metastasis
- FOXO transcription factor regulation
- Wnt/β-catenin signaling in development and cancer
- Cellular transport and secretion
Medical College of Wisconsin
2017-2025
Children's Hospital of Wisconsin
2017-2022
Center for Vascular Biology Research
2010-2020
Boston Children's Hospital
2009-2019
Harvard University
2009-2019
Insigneo
2016
University of Sheffield
2016
Imperial College London
2016
Boston Children's Museum
2015-2016
KU Leuven
2016
Here, we describe a biomimetic microsystem that reconstitutes the critical functional alveolar-capillary interface of human lung. This bioinspired microdevice reproduces complex integrated organ-level responses to bacteria and inflammatory cytokines introduced into alveolar space. In nanotoxicology studies, this lung mimic revealed cyclic mechanical strain accentuates toxic silica nanoparticles. Mechanical also enhances epithelial endothelial uptake nanoparticulates stimulates their...
The Rho GDP dissociation inhibitor (GDI) forms a complex with the GDP-bound form of family small G proteins and inhibits their activation. complexed GDI is not activated by GDP/GTP exchange factor for members, suggesting presence another necessary this We have reported that subfamily members regulate ezrin/radixin/moesin (ERM)-CD44 system, implicated in reorganization actin filaments. Here we report directly interacts ERM, initiating activation reducing activity. These results suggest ERM as...
Fundamental investigations of human biology, and the development therapeutics, commonly rely on 2D cell-culture systems that do not accurately recapitulate structure, function, or physiology living tissues. Systems for 3D cultures exist but replicate spatial distributions oxygen, metabolites, signaling molecules found in Microfabrication can create architecturally complex scaffolds cell circumvent some these limitations; unfortunately, approaches require instrumentation available biology...
Cyclic mechanical strain produced by pulsatile blood flow regulates the orientation of endothelial cells lining vessels and influences critical processes such as angiogenesis. Mechanical stimulation stretch-activated calcium channels is known to mediate this reorientation response; however, molecular basis remains unknown. Here, we show that cyclically stretching capillary adherent flexible extracellular matrix substrates activates mechanosensitive TRPV4 (transient receptor potential...
Pulmonary thrombosis is a significant cause of patient mortality; however, there are no effective in vitro models thrombi formation human lung microvessels that could also assess therapeutics and toxicology antithrombotic drugs. Here, we show microfluidic alveolus‐on‐a‐chip lined by primary alveolar epithelium interfaced with endothelium cultured under flowing whole blood can be used to perform quantitative analysis organ‐level contributions inflammation‐induced thrombosis. This chip...
Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs raise EET levels in clinical trials for the treatment of hypertension many other diseases. However, despite their pleiotropic effects on cells, little is known about role these epoxyeicosanoids cancer. Here, using genetic pharmacological manipulation endogenous levels, we...
Here we describe a combined microfluidic-micromagnetic cell separation device that has been developed to isolate, detect and culture circulating tumor cells (CTCs) from whole blood, demonstrate its utility using blood mammary cancer-bearing mice. The was fabricated polydimethylsiloxane contains microfluidic architecture with main channel redundant ‘double collection’ lined by two rows of dead-end side chambers for collection. microdevice design optimized computational simulation determine...
Integrins are ubiquitous transmembrane mechanoreceptors that elicit changes in intracellular biochemistry response to mechanical force application, but these alterations generally proceed over seconds minutes. Stress-sensitive ion channels represent another class of activated much more rapidly (within msec), and recent findings suggest calcium influx through Transient Receptor Potential Vanilloid-4 (TRPV4) expressed the plasma membrane bovine capillary endothelial cells is required for...
Significance Interstitial flow (IF) is elevated in solid tumors and imparts fluid stresses on tumor cells within the extracellular matrix (ECM), these must be balanced by stress adhesions to maintain static equilibrium. This force balance results greater adhesion tension upstream side of cell, we demonstrate that this activates β1-integrin complexes, resulting localization activation focal (FA) proteins near membrane. Importantly, asymmetric FA governs direction cell migration 3D, therefore...
Cell shape-dependent control of cell-cycle progression underlies the spatial differentials growth that drive tissue morphogenesis, yet little is known about how cell distortion impacts biochemical signaling machinery responsible for control. Here we show Rho family GTPase, RhoA, conveys “cell shape signal” to in human capillary endothelial cells. Cells accumulating p27kip1 and arrested mid G1 phase when spreading were inhibited by restricted extracellular matrix adhesion, whereas...
In vitro 3D culture is an important model for tissues in vivo. Cells different locations of are physiologically different, because they exposed to concentrations oxygen, nutrients, and signaling molecules, other environmental factors (temperature, mechanical stress, etc). The majority high-throughput assays based on cultures, however, can only detect the average behavior cells whole construct. Isolation from specific regions cultures possible, but relies low-throughput techniques such as...
Tumor blood vessels exhibit abnormal structure and function that cause disturbed flow high interstitial pressure, which impair delivery of anti-cancer agents. Past efforts to normalize the tumor vasculature have focused on inhibition soluble angiogenic factors, such as VEGF; however, capillary endothelial (CE) cell growth differentiation during angiogenesis are also influenced by mechanical forces conveyed extracellular matrix (ECM). Here, we explored possibility CE cells form because they...
Glioblastoma is a highly vascularized brain tumor, and antiangiogenic therapy improves its progression-free survival. However, current induces serious adverse effects including neuronal cytotoxicity tumor invasiveness resistance to therapy. Although it has been suggested that the physical microenvironment key role in angiogenesis progression, mechanism by which properties of extracellular matrix control glioblastoma progression not completely understood. Herein we show compaction (the...
Angiopoietin-1 (Ang-1), a ligand of the endothelium-specific receptor Tie-2, inhibits permeability in mature vasculature, but mechanism remains unknown. Here we show that Ang-1 signals Rho family GTPases to organize cytoskeleton into junction-fortifying arrangement enhances barrier function endothelium. phosphorylates Tie-2 and its downstream effector phosphatidylinositol 3-kinase. This induces activation one endogenous GTPase, Rac1, inhibition another, RhoA. Loss either part this dual...
The actin cross-linking protein filamin A (FLNa) functions as a scaffolding and couples cell cytoskeleton to extracellular matrix integrin receptor signaling. In this study, we report that FLNa suppresses invasion of breast cancer cells regulates focal adhesion (FA) turnover. Two large progression tissue microarrays from patients revealed significant decrease levels in tissues invasive compared with benign disease lymph node-positive node-negative cancer. orthotopic mouse models,...
Blood flow influences atherosclerosis by generating wall shear stress, which alters endothelial cell (EC) physiology. Low stress induces dedifferentiation of EC through a process termed endothelial-to-mesenchymal transition (EndMT). The mechanisms underlying stress-regulation EndMT are uncertain. Here we investigated the role transcription factor Snail in low stress-induced EndMT. Studies cultured exposed to revealed that induced expression. Using gene silencing it was demonstrated...