Medical Research

Stanford University

Helen Blau, Sarah Heilshorn
Palo Alto, CA
December 2020

Cells are constantly receiving and responding to diverse signals from their microenvironment.  Aberrant environmental cues, such as increased tissue stiffness from disease-related fibrosis, can drive disease progression.  Genetic disorders that alter how cells interact with the extracellular environment make cells particularly sensitive to changes in environmental cues.  One such disease, Duchenne muscular dystrophy (DMD), is caused by defective dystrophin, a protein that links the cytoskeleton and the extracellular matrix.  DMD manifests as severe muscle wasting followed by dilated cardiomyopathy, leading to patient death around 20-30 years of age.  A Stanford University team has recently identified telomere shortening as a hallmark of DMD cardiomyopathy, as well as of other heritable cardiomyopathies, leading the investigators to postulate that telomere shortening plays a causal role in heart failure in many genetic diseases.  However, this hypothesis is controversial, given that telomere shortening has historically been associated with cell division, and cardiomyocytes do not divide.  The investigators will determine whether mechanical stress drives telomere shortening and subsequent pathogenic signaling, leading to cardiomyocyte death.  They have developed a novel hydrogel platform that can be stiffened and softened on demand to tune mechanical load, which will be used in conjunction with human induced pluripotent stem cell derived cardiomyocytes from DMD patients and live cell imaging to answer the fundamental question: How can telomeres shorten without cell division?

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