IN BRIEF: The Sanders Lab at UT Southwestern seeks to understand how molecular networks control cellular states, and how related pathways are hijacked by diseases of aging. Collectively, our work has informed how physiological liquids and pathological solids form according to the molecular interactions of their components. The majority of our current efforts are dedicated to understanding the role of vertebrate-specific liquid compartments in RNA homeostasis, particularly in the context of neurodegenerative and neuromuscular diseases.

Our group has grown rapidly over the past several months and our research focus has similarly expanded! We are still actively recruiting graduate students. If you have an insatiable thirst for destroying dogma, please reach out to David to discuss career opportunities and/or collaboration!

See Projects and Publications for details on current and past work.

RESEARCH SUMMARY: Our scientific efforts dismantle complex problems on molecular assemblies into modular building blocks for bottom-up reconstitution in living cells. Of primary interest are the peculiar liquid-like compartments that pattern the living cell. Over the past decade, these compartments (‘condensates’) were shown to form by biological phase transitions, but the function of most remains contentious. Condensates were further linked to neuromuscular diseases and cancers, which makes them attractive drug targets. However, drug design and functional understanding both require a model that makes accurate predictions as to how cellular condensates selectively assemble and regulate their dozens of unique proteins and RNAs (‘composition’) . In absence of a model, condensate function (e.g., RNA processing, signaling) is typically inferred from test tube studies that rarely reflect their regulated complex composition in vivo. Still, functional studies in live cells remain rare, as tools to control condensate assembly and composition are lacking. Our research addresses these needs, using new tools to provide a model for condensate assembly and composition in living cells. Despite their complexity, cellular condensates follow a simple code, based on specific interactions (‘valence’, v) made between their molecules. This ‘network model’ deconstructs condensates into molecular wiring diagrams (‘networks’), which feature biomolecules that hold the network together (‘nodes’, v≥3) and others that destroy it (‘caps’, v=1).

Central to our model’s predictive power is the protein node’s folded oligomerization domain, where multiple proteins compete at a single binding site for control over the network. The winner of this molecular tug of war not only determines whether a condensate forms, but if so, the molecules it contains (‘wiring’) and the reactions it performs (‘function’). Based on this model, we hypothesize that: (1) condensates are rewired to regulate RNA homeostasis in cellular differentiation; (2) miswiring causes failures in RNA homeostasis and diseases of aging. Our lab is actively testing these hypotheses, applying a proven workflow for dissecting molecular networks to skeletal muscle, chosen for its unique condensates, RNA processing requirements, and disease relevance. We envision that our initial efforts to understand muscle development and degeneration will guide long-term efforts to determine how network rewiring controls cell fate decisions and diverse diseases of aging.

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REACH OUT! We are always looking for collaborators! Email David! Or send David a message on your preferred networking platform if you have something interesting to say. He might have something interesting to say in response. He might not.