Projects

Mentor: Professor Michael Greenberg

The Greenberg lab focuses on how cytoskeletal motors function in both health and in diseases such as familial cardiomyopathies, the leading cause of sudden cardiac death in people under 30 years old. These diseases are characterized by cardiac tissue responding to stress with increased fibrosis; however, it is not clear how point mutations at the molecular level lead to these changes that cause permanent memory of mechanical force.

REU Project:
The student will examine how changes in the mechanical environment of the heart due to fibrosis cause permanent changes to the structural and contractile properties of cardiomyocytes with familial cardiomyopathy mutations. We hypothesize that cells with familial cardiomyopathy mutations will show aberrant responses to changes in the mechanical environment that could eventually lead to tissue remodeling. To test this hypothesis, the student will grow stem cell-derived cardiomyocytes bearing disease-causing mutations on hydrogels with stiffnesses that mimic healthy and fibrotic hearts, then use traction force microscopy to measure the force, power, and velocity of contraction as a function of time. They will compare these parameters between healthy and mutant cardiomyocytes to see whether substrate stiffness affects contractility in mutant cells. The student will additionally learn an array of biochemical, biophysical, and cell biological techniques to address this gap in our knowledge.

Mentor: Professor S. Celeste Morley

Macrophages, cells critical to immune responses, have been shown recently to be mechanosensitive and to change permanently in response to mechanical stimuli. The Morley lab hypothesizes that the actin-bundling protein L-plastin (LPL) supports mechanoregulation of the inflammasome (NLRP3), and is testing this hypothesis in alveolar macrophages, which are lung-resident phagocytic cells that are the immune system’s first responders to inhaled pathogens such as SARS-CoV-2. Failure of activation can lead to death or long-term disability due to pulmonary fibrosis following inhalation of pathogens (e.g. SARS-CoV-2) or irritants (e.g. asbestos).

REU Project:
The student will test the hypothesis that  mechanotransduciton through integrin-mediated podosomes directly regulates theamount of IL-1beta produced after NLRP3 inflammasome activation, and that LPL forms an essential link in transmitting this signal. The student will incubate primary mouse macrophages of defined stiffness and test IL-1beta production after NLRP3 activation compared to controls. Results would illuminate a mechanism of locking mechanical memory into macrophages via activation, and possibly illuminate new targets for treatment of pulmonary diseases.

Mentor: Professor Lori Setton

Intervertebral disc (IVD) disorders are a major source of disability arising from nucleus pulposus (NP, Fig. 3) cells changing phenotype and morphology, possibly in response to pathological mechanosensation. Immature NP cell-ECM interactions may regulate cell phenotype, metabolism and morphology; ECM stiffness can also regulate cell biosynthesis and morphology.

REU Project:
The student will study NP cell-ECM interactions to reveal how ECM cues can be manipulated, and to engineer new biomaterials that can  cause cells to forget previous mechanical insults and promote regeneration in the injured or pathological IVD. We hypothesize that a soft, laminin-containing substrate will promote repair and regeneration in an animal model of disc degeneration. Students will learn tissue characterization and evaluation of therapeutic outcomes for cell delivery to treat IVD-related disorders.