Membrane biophysics and biochemistry in human health and disease.
Our lab is broadly interested in building a comprehensive understanding of inflammation, lipid transport, and metabolism in human health and disease. We are currently working on three major research directions, which are described below.
Tau aggregates (green) on the surface of lysosomes (magenta)
Real-time, membrane permeabilization assay
Light-induced fluorescence conversion
Time-dependent proton leakage from lysosomes (white)
1
Decoding the Cellular Roots of Neurodegeneration
Neurodegenerative diseases represent one of the most urgent biomedical challenges of our time, with a rapidly aging global population and no effective treatments. A major obstacle in developing successful therapies has been the tendency to target symptoms rather than the root causes of disease progression.
At the Shukla lab, we are driven by a central question: How do disruptions in the function of individual organelles trigger irreversible cell death in the brain? We focus on uncovering the fundamental molecular events—both intrinsic and environmentally triggered—that compromise organelle health and lead to dysfunction across diverse brain cell types, including neurons, glia, and microglia.
To tackle this complex problem, we integrate in vitro reconstitution, live-cell imaging, and collaborative structural approaches, enabling us to dissect cellular pathways with precision and clarity. Our long-term goal is to illuminate the molecular circuitry underlying neurodegeneration and uncover new therapeutic entry points for intervention.
Lipid Transport and Metabolism in Human Health and Disease
Lipids are essential regulators of cellular function, influencing everything from membrane structure and signaling to immune responses and metabolism. Proper lipid transport—both within and between cells—is critical for maintaining homeostasis across organ systems. Yet, the molecular rules governing these processes remain poorly understood.
Our lab investigates how lipid transporters, membrane mechanics, and protein-lipid interactions coordinate to ensure efficient lipid trafficking. We use a multidisciplinary approach that combines membrane reconstitution, live-cell imaging, and biophysical manipulation to model lipid loading and transfer with precision.
By integrating membrane biophysics with cell biology, we aim to uncover fundamental principles of lipid homeostasis and how their disruption contributes to disease. This knowledge will inform new strategies to target lipid-related disorders, from neurodegeneration to cardiovascular and metabolic diseases.
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3
Cracking the Code of Tau Seed Propagation
Tauopathies, including Alzheimer’s disease and related neurodegenerative disorders, are defined by the abnormal accumulation and spread of tau protein aggregates in the brain. While structural differences among tau assemblies are linked to disease-specific symptoms, the precise mechanisms by which these aggregates breach cellular barriers and propagate remain poorly understood.
Our lab focuses on uncovering how distinct tau assemblies interact with intracellular membranes—a critical, underexplored step in their spread. By building systems that recapitulate key aspects of tau behavior in controlled environments, we aim to reveal the principles that govern their movement across compartments and between cells.
Through this work, we seek to expose the molecular underpinnings of tau pathology and identify new vulnerabilities that could be targeted in future therapeutic strategies. While our primary interest lies in tauopathies, insights from this research may also shed light on the broader class of protein misfolding disorders.
Funding
