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Research Areas

 

Research Areas

Cells use actin filaments in the cytoskeleton to provide structural strength, generate movements, and coordinate shape and adhesion to form tissues and organs. Actin filaments are intrinsically polarized, with distinct fast growing (barbed) and slow growing (pointed) ends. Unlike the highly stable beams used to construct buildings, actin filaments are dynamic polymers, with subunits that come on and off their ends.  Our research aims to unravel how temporal and spatial control of actin dynamics creates the diverse cytoskeletal structures that determine cell and tissue architecture, physiology and pathology.

Since the discovery of tropomodulins (Tmods), as a family of actin filament (F-actin) pointed end capping proteins by our lab, we continue to study Tmods and related family members, leiomodins (Lmods), together with their F-actin binding partners and co-regulators. Tmods are a family of actin-capping proteins that inhibit actin association and dissociation at the slow-growing (pointed) ends of actin filaments. There are four canonical, ~40 kD tropomodulin isoforms (Tmods1-4) in vertebrates, with tissue-specific and developmentally regulated patterns of expression. Tmods also bind tropomyosin (TM) isoforms, which bind along the sides of actin filaments and protect them from disassembly and mechanical breakage. Working in concert with Tmods and TMs, non-muscle myosins (NMIIs) pull on TM-coated F-actin to exert contractile forces. Some Tmods can also bind actin monomers and nucleate actin filament assembly, providing another point of actin dynamics regulation. In addition, the three larger, ~70 kD Tmod family variants, the leiomodins (Lmods1-3), contain a C-terminal extension and potent actin-nucleating activity. Tmods are essential for embryonic development and viability, while mutations in Lmod1 or Lmod3 do not interfere with development but lead to impaired smooth or skeletal muscle contractility in the human diseases of megacystis microcolon intestinal hypoperistalsis syndrome or nemaline myopathy, respectively.

We currently study three cell types: red blood cells (RBCs), megakaryocytes (MKs), and the ocular lens. In these cells, we study the diverse and cooperative functions of Tmods, TMs, and NMIIs that affect F-actin on cell membranes, providing stability and exerting contractile forces to shape membrane curvature and influence cell and tissue biomechanical properties. We strive to perfect classical methods and develop novel protocols to study cell and tissue properties. Our wide ranging approaches include biochemistry and biophysics, conventional and super-resolution fluorescence microscopy, live cell imaging, mouse genetics and physiology, and analysis of human cells from patients with congenital diseases, allowing us to study physiology, aging and pathology from the macro to the micro scale.

Overarching questions are:

(1) What are the common and diverse molecular mechanisms that specify actin filament architecture and function in cells and tissues?

(2) What insights can mutations and genetic perturbations provide into normal tissue development and physiology, and what are the pathological mechanisms of actin dysregulation in human aging and disease?

When answering these questions, our multidisciplinary and multi-scale approach allows us to connect the dots — from actin dynamics regulation, to organization of cytoskeletal structures in cells, to morphogenetic differentiation during development, to cell and tissue physiology in health and disease.