Research

Our lab investigates the role played by cytoskeletal proteins in maintaining cellular homeostasis and the mechanistic basis of cytoskeleton-associated neurological, metabolic, and muscular disorders. We seek to understand how the assembly and dynamic coordination of cytoskeletal networks in specialized cell types contribute to the regulation of signal transduction, intracellular trafficking, cell motility, membrane dynamics, and cellular metabolism.

Our current projects center on the cytoskeleton-associated families of proteins ankyrins, spectrins, and associated partners. Ankyrins act as micron-scale organizers of functionally related membrane transporters and cell adhesion proteins. Ankyrin-B, an ankyrin family member, is a regulator of intracellular transport in multiple cell types. Ankyrins are coupled to arrays of partnering spectrins, which confer mechanical resiliency to cell membranes. In mammalians, ankyrins and spectrins are widely expressed across multiple tissues, where they serve specialized functions. However, we do not fully understand the molecular mechanisms underlying these functions, their physiological consequences, or how their dysregulation cause disease.

We are currently studying the neurobiological and metabolic roles of ankyrins, spectrins, and associated partners.

Neurobiology

Ankyrins and spectrins are widely expressed in the brain, where they display varied tissue specificity, subcellular localization, and functional specialization. Interestingly, the giant ankyrin isoforms are selectively expressed in the nervous system and have specialized roles in axons. Ankyrins variants have been associated with autism spectrum disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BD). Loss of ankyrin-B results in deficits in axonal transport, shortened axonal tracts, and agenesis of the corpus callosum (CC) in mice.

βII-spectrin, an ankyrin partner, promotes the formation of a submembrane periodic actin network in axons. Interestingly, loss of βII-spectrin also results in impaired axonal transport, reduced axonal length, loss of the CC, and abnormal mouse brain connectivity. Mutations in spectrins cause Spinocerebellar Ataxia Type 5 (SCA5) (β-III spectrin) and have been associated with the West syndrome (α-II spectrin). We are trying to understand how deficiencies in ankyrins and spectrins result in aberrant neurodevelopment and wiring of the central nervous system, and lead to a wide range of behavioral, motor, and sensorial deficits.

Metabolism

Mounting evidence indicates that ankyrins play critical roles in metabolic homeostasis across different organs. Furthermore, ankyrins’ relevance in metabolism is accentuated by the recurrent identification of ankyrin variants as risk factors for obesity, T2D, and other metabolic disorders in multiple ethnic populations. However, the specific roles of ankyrins in signaling mechanisms regulating cellular bioenergetics and metabolic function remain unclear.

Rare variants in ankyrin-B, cumulatively carried by an estimated 6.5M Americans, have been linked to cardiac arrhythmias and found enriched in type 2 diabetes (T2D) patients. We recently reported that knock-in mice bearing human AnkB variants develop primary pancreatic β-cell insufficiency combined with age- or diet-dependent obesity and insulin resistance (IR). Furthermore, mice expressing these disease-associated AnkB variants show altered localization of the insulin-responsive glucose transporter 4 (GLUT4) in adipocytes and skeletal muscle cells, and altered glucose uptake. AnkB loss in white adipose tissue (WAT) alters glucose disposal and causes cell-autonomous adiposity, systemic inflammation, and IR in mice. We are currently investigating the underlying mechanisms of the metabolic roles of ankyrins in different tissues, and how human ankyrin variants might lead to obesity, diabetes, and metabolic syndrome.