Henk L. Granzier
University of Arizona, AZ·Physiology
Muscle contracts because of a precisely built repeating unit called the sarcomere, in which thin filaments slide against thick filaments. Two unusually large proteins act as the sarcomere's rulers and springs: nebulin, which runs along the thin filament and binds actin, and titin, which spans from the middle of the sarcomere to its boundary and behaves like a molecular spring.
- Fields
Physiology
Biochemistry
Medicine & Clinical Research
- Topics
nebulin
titin
sarcomere
- Grants
- 3 known grants, through Jun 2029
What they work on
- Determine whether the dominant nebulin deletion NEBΔ14–89 accumulates because of more transcript or more efficient translation, quantifying RNA and protein in patient biopsies and using ribosome profiling (Ribo-seq) to measure translational output, with STORM super-resolution imaging and contractile assays for structural and functional effects.
- Measure how fast nebulin is replaced in living adult muscle using mice with Dendra2-tagged nebulin, a tag that permanently switches color on illumination, imaged for months through surgically implanted windows, and compare cytosolic versus filament-incorporated pools across deletion variants by single-molecule localization microscopy.
- Test whether allele-specific knockdown with short hairpin RNA against the mutant NEBΔ14–89 transcript rescues myopathy in mice, as a candidate therapeutic strategy for dominant nebulin disease.
- Test the dual thin filament length regulation model in slow muscle, in which nebulin sets a proximal segment and leiomodin-2 (Lmod2) sets a distal nebulin-free segment, and ask whether raising Lmod2 treats severe nebulin-based nemaline myopathy in mouse models.
- Determine why nebulin's centrally located super-repeats bind actin weakly, using mice in which these weak-binding repeats are converted to strong binders and assessing intact muscle by mechanical assays and low-angle X-ray diffraction.
- Map the layout of nebulin's C-terminus within the Z-disk, locate its alternatively spliced Z-repeats, identify binding partners, and test how deleting differentially expressed Z-repeats alters Z-disk structure and muscle function.
- Define how titin's PEVK spring segment and N2A region regulate stiffness in activated skeletal muscle, including the effect of upregulating the stress-response protein MARP1, using mouse models.
- Test whether titin-based passive force strains the thick filament and thereby converts myosin from the super-relaxed (SRX) to the disordered-relaxed (DRX) state, switching thick filaments on, using high-resolution ATP turnover assays.
- Determine the relative contributions of titin and MyBP-C to the high level of super-relaxed myosin in the sarcomere's C-zone, and test how deleting single C-zone domains to locally perturb titin strain changes SRX.
More about the research
Mutations in either protein cause disabling muscle diseases, yet because the proteins are giant they have been hard to study. Work across these projects asks how nebulin sets filament length and gets replaced over time, how different disease-causing nebulin variants break those processes, and how titin's stiffness not only resists stretch but actively helps switch the contractile machinery on. The approaches span single molecules to whole muscle, using genetically engineered mouse models, patient biopsies, super-resolution imaging, X-ray diffraction and mechanical testing.
Why it matters
Mutations in nebulin and titin cause congenital and other myopathies, including nemaline myopathy type 2, for which no effective treatments exist. Identifying the mechanisms — faulty thin filament length regulation, slowed replacement of mutant protein, or altered titin-based stiffness and thick filament activation — points to concrete intervention points, such as raising leiomodin-2 or silencing a mutant NEB transcript with shRNA, that could be developed into therapies for patients with these muscle diseases.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Srinivasa Subramaniam
Florida Atlantic University, FL·Neuroscience
Identify the protein and RNA components on ribosomes that interact with mutant huntingtin (mHTT), the toxic protein that causes Huntington disease, using biochemical approaches.
Anthony Cammarato
Johns Hopkins University, MD·Physiology
Test whether acetylation of actin residues K326 and K328 — sites previously shown by this group to bind and orient the regulatory protein tropomyosin — shifts tropomyosin away from its contraction-blocking position and enhances cardiac performance, using recombinant human proteins, flies and mice.
Alexander S Mankin
University of Illinois Chicago, IL·Microbiology & Immunology
Optimize small-molecule inhibitors of peptidyl-tRNA hydrolase, the bacterial enzyme that recycles unfinished protein chains, by synthesizing derivatives of sub-micromolar hits for stronger activity against the Klebsiella pneumoniae enzyme and better uptake into cells.
The school
University of Arizona: 36 labs on PI Pages, $1.0B a year on research, 487 research doctorates a year.
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