Project Details
Description
Project Summary
The Dystrophin-Associated-Protein-Complex (DAPC) is an important transmembrane protein complex that
structurally, mechanically, and functionally links cytoskeleton and the extracellular matrix and serves as both
mechanical and signaling hubs in regulating muscle and non-muscle cells. Mutations affecting DAPC
components are associated with a wide range of diseases such as muscular dystrophies. Although there is a
wealth of knowledge on the DAPC composition, the mechanisms underlying how the DAPC senses and adapts
to biochemical, mechanical, and topographic cues in cell microenvironments and consequently regulates cell
phenotypes and functions remain unknown. We recently discovered that substrates patterned with submicron
ridges/grooves and functionalized with Matrigel or laminin present an engineered cell microenvironment to
allow myotubes derived from non-diseased human induced pluripotent stem cells (hiPSCs) to align nearly
perpendicular to the ridges, while myotubes derived from less-affected and severely-affected Duchenne
Muscular Dystrophy (a genetic disorder resulting from mutations in dystrophin and often leading to death at an
age of 20-30s due to cardiac and respiratory failure) cells exhibit prominent differences in alignment and
orientation, providing a sensitive phenotypic biomarker to distinguish these cells, which may serve as a
phenotypic readout for high throughput therapy development. Our preliminary data suggest that this
nanotopography-responsive myotube orientation is regulated by the DAPC; however, details of how
nanotopography regulates myotube orientation through the DAPC are unclear. We hypothesize that the
perpendicular myotube orientation is caused by structural adaption of the anisotropic DAPC on the
nanotopography to remain its stability. We expect that super-resolution Single Molecule Localization
Microscopy (SMLM) will enable us to examine the DAPC nanoarchitecture and its structural adaption in
response to nanotopography and verify our hypothesis. Successful accomplishment of this project will reveal
unprecedented nanoscale details of the DAPC, DAPC structural adaption on nanotopography, and the
mechanism underlying the nanotopography-responsive myotube orientation, which are all unknown currently.
This project will lay the foundation for future studies that combine SMLM and biomaterials engineering to
elucidate more mechanistic details underlying DAPC-mediated force transmission, mechanosensing, and
mechanochemical transduction in normal muscle function and in various muscular and neuromuscular
disorders. Verification of the role of the DAPC in regulating nanotopography-responsive myotube orientation
may extend it as a phenotypic biomarker for many other muscular dystrophies associated with defective DAPC
components. This study will also reveal novel engineering approaches to regulate cell behavior and cell fate
through topographic control of the DAPC.
Status | Active |
---|---|
Effective start/end date | 9/20/23 → 8/31/25 |
Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $354,222.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.