Matter Lab

Matter Lab 

Researchers in the Matter Lab investigate the regulation of cell survival and apoptosis by cell adhesion in cardiovascular disease.


Top (l-r): Michell Matter, Ph.D. (Assistant Professor), Genevieve S. Griffiths, Ph.D. (Postdoctoral Researcher), Anna Leychenko, M.S. (Research Associate)

Current Research

Our lab is interested in the regulation of cell survival and apoptosis (programmed cell death) by cell adhesion.  In particular we study signal transduction pathways activated by integrin-mediated adhesion in cells of the cardiovascular system.  Integrins are cell adhesion receptors that bind to extracellular matrix proteins such as collagen, laminin, and fibronectin.  They are found on all cells of the body and activate a number of signal transduction pathways upon ligation. Our primary research focus is on signal transduction pathways activated by integrin-mediated adhesion (outside-in signaling) in the heart. We have shown previously that integrin activation of PI3-kinase leads to increased Bcl-2 transcription and subsequent increased protein expression in many cell types. Once activated this pathway protects cells from apoptosis. The lab has several ongoing projects that investigate integrin-mediated signaling in cardiovascular disease.

1. Integrin-mediated signaling in the heart

As a first step to identify novel regulators of the anti-apoptotic protein Bcl-2, Dr. Matter used expression cloning to isolate proteins that could modify Bcl-2 expression. One such protein is Bit-1, which we have previously shown is an effector of anoikis (apoptosis due to loss of integrin-mediated cell attachment) upon placing cells in suspension. The anoikis function of Bit-1 is only counteracted by integrin-mediated cell attachment. We are investigating the function of integrins and Bit-1 in the heart.

2. Bit-1 Knockout Mice

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Bit-1 null mice die at day 8 after birth and present with an altered heart morphology and function. We are currently examining the role of Bit-1 in both normal heart function and in cardiovascular disease. We are also developing a heart-specific Bit-1 knockout mouse that will be instrumental in identifying the role of Bit-1 in cardiac muscle and heart function.

3. The role of the R-Ras/Filamin A complex in regulating vascular permeability

Coronary heart disease is the number one cause of death in the United States and affects 17.6 million Americans. It often leads to an acute myocardial infarction (MI) of which 8.5 million Americans suffer each year with approximately 500,000 of these being fatal. An acute MI can be exacerbated by edema that promotes fluid accumulation in the heart tissue, causes an enhanced inflammatory response and induces fibrosis. Over time this can lead to heart failure, which afflicts over 5 million people each year. Preventing or reversing the vascular permeability that results after heart attack and stroke is an area that we are actively investigating. 

(click on image to enlarge)

We have identified a novel mechanism by which vascular barrier integrity is maintained. We have previously reported an interaction between R-Ras and Filamin A (FLNa).  R-Ras, an intracellular GTP-binding protein, is primarily expressed in endothelial cells in vivo and is a regulator of arterial endothelial function. The cytoskeletal protein FLNa is required for cell-cell contact in vascular development. Indeed, FLNa-null mice die of vascular defects. We find that in arterial endothelial cells endogenous R-Ras interacts with endogenous FLNa. Furthermore, endothelial barrier function is dependent upon active R-Ras and an association between R-Ras and FLNa. We hypothesize that the R-Ras/FLNa complex is an important component in forming and maintaining endothelial barrier function in the cardiovascular system. We are currently working to elucidate this mechanism further and thereby identify potential new therapeutic targets that promote vascular integrity. 

4.Stretch-mediated signaling in cardiomyocytes

Cardiovascular diseases such as hypertension and myocardial infarction are associated with the onset of hypertrophy.  Hypertrophy occurs as a compensatory response mechanism to an increase in mechanical load due to pressure or volume overload. It is characterized by extracellular matrix remodeling and hypertrophic growth of cardiomyocytes. We are investigating whether cyclic mechanical stretch that induces hypertrophic responses activates          
integrin-mediated signaling cascades.                   (click on image to enlarge)
Using an in vitro model of cultured primary adult rat cardiac myocytes subjected to cyclic mechanical stretch we can measure a number of signaling components. We are currently researching integrin-mediated signaling through FAK-NFκB that is initiated in response to stretch and may ultimately coordinate the hypertrophic response in ARCMs.

  Contact Information

  Dr. Michelle Matter
  Assistant Professor
  Phone: 808-692-1522