DISEASE STATES
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RENAL FIBROSIS
Chronic Kidney Disease (CKD) affects nearly 1 in 20 Americans, and the prevalence of the disease is growing. Renal failure from CKD is due to excessive fibrosis in the kidney. Fibrosis is the excess assembly of extracellular matrix (ECM) proteins. One of the primary ECM proteins that is upregulated in fibrosis is fibronectin. Fibronectin is secreted in a soluble form and is assembled by cells into insoluble, viscoelastic fibrils. These fibrils not only have unique mechanical properties from native tissue, but also serve as a reservoir for pro-fibrotic growth factors such as TGF-beta. We are investigating the cross-talk between renal epithelial cells and renal fibroblasts to dissect the signaling misinformation that drives a self-sustaining feedback loop of fibronectin matrix assembly in renal fibrosis, with the hope of developing targetable steps in the pathway as a means to treat renal fibrosis and Chronic Kidney Disease. |
TUMOR MICROENVIRONMENT
The inflammatory cytokine TGF-beta and the transmembrane family of integrins are both misregulated in the tumor microenvironment and have been extensively targeted in cancer clinical trials. However, despite their known roles and myriad attempts to clinically target them, most clinical trials have failed, and no therapeutics that target either TGF-beta or integrins have been approved in cancer. Our lab believes that there is an understudied and underappreciated cross-talk between these pathways in the tumor microenvironment, and that better understanding of this cross-talk could drive improved targeting of both pathways in cancer. Distinct subsets of integrins bind to fibronectin fibrils and to TGF-beta that is tethered to the fibrils. Integrins bind to the latency-associated peptide of TGF-beta, which both releases the active TGF-beta and triggers downstream integrin signaling. We are developing new computational and experimental models to probe this crosstalk and potentially devlop new therapeutic avenues. |
PREMATURE RUPTURE OF AMNIOTIC MEMBRANES (P-PROM)
Preterm birth (PTB) is the leading cause of neonatal and infant death; 15 million preterm births occur worldwide annually. Spontaneous preterm premature rupture of membranes (PPROM) occurs in ~40% of spontaneous preterm births. PPROM is caused by a weakening of the amniotic membrane. Amniotic epithelial cells experience an epithelial-mesenchymal transition (EMT) during this process; EMT is typically associated with increased extracellular matrix deposition, so this finding is counterintuitive. Our lab, in conjunction with the Jefferson Lab at VCU Health, is quantifying mechanical properties of healthy and PPROM amniotic membranes, while also developing a tissue-engineered human amnion as a testbed for future pre-clinical investigations. |
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IN VITRO TISSUE MIMETICSAssembly of extracellular matrix is highly dependent on the cells involved, the spatial organization of those cells, and the mechanical properties of the surrounding tissue. We are generating 3D tissue mimetics in order to study fibrotic signaling in a tissue-relevant scenario. These mimetics include renal tubule spheroids, cell sheet-engineered amniotic membranes, and tumor organoids. |
COMPUTATIONAL mODELSComputational models allow us to investigate how a mechanistic theory might affect outcomes of fibrosis. We use preliminary data from in vitro tissue mimetics to train the models, predict fibrotic outcomes based on computational simulations, and then validate these outcomes via tissue mimetics. Modeling efforts include 3D agent-based models, hybrid stochastic-deterministic signaling models of cellular contractile forces, biophysical models of fibronectin fibril assembly, differential equation-based models of integrin/TGF-beta crosstalk, and Cellular Potts models of 2D cell-matrix interactions. |
NOVEL INHIBITORSA substantial number of clinical trials have targeted either integrin signaling or TGF-beta signaling; however, there are only limited examples of approval of therapeutics that target these pathways. We believe that this is due to an incomplete understanding of how these pathways interact in fibrotic signaling. We are investigating novel inhibitory modalities to better target these pathways in fibrosis and cancer. |
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Our Story |
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The Lemmon Lab at Virginia Commonwealth University specializes in cell-matrix mechanobiology. Our lab is interested in how cells assemble extracellular matrix to achieve the desired mechanical properties and signaling events necessary to promote cell attachment, organization, and function in tissues. We are also interested in dysregulation of this process in various disease states, including cancer, diabetes, and birth defects. We investigate these questions using an array of tools, including novel microfabricated structures that serve as a scaffold for ECM assembly and allow for measurement of cell-derived forces, proliferation, and migration in vitro; novel substrates with defined viscoelastic properties; and novel biological inhibitors of provisional matrix assembly and signaling.
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