Projects

Project I: Deciphering Metal-Directed Molecular Networks in Neurodegenerative Diseases

Neurodegenerative diseases arise from interconnected molecular processes involving metal ions, amyloidogenic peptides and proteins, neuropeptides and neuron-related proteins, small-molecule neurotransmitters, reactive oxygen species (ROS), and inflammatory mediators. Metal ions are particularly important components of these networks because their coordination and redox chemistry can alter protein structure and function, protein–protein interactions, aggregation and phase transitions, oxidative reactivity, and cellular toxicity.

The Lim Laboratory investigates how metal homeostasis, coordination, and redox reactivity are integrated with disease-associated biomolecular networks at the molecular level. We seek to identify previously unrecognized interactions among metal ions, endogenous small molecules, neuropeptides and proteins, and amyloidogenic species and to determine how these interactions reshape their structures, reactivities, and biological functions. By integrating bioinorganic chemistry with biochemical, biophysical, computational, cellular, and in vivo approaches, we aim to establish fundamental chemical principles that connect metal-directed molecular events to the pathogenesis of neurodegenerative diseases.

Project II: Chemical Tools for Interrogating and Controlling Metal-Linked Pathological Networks

Aberrant interactions between metal ions and amyloidogenic proteins can profoundly alter protein aggregation, oxidative reactivity, and neurotoxicity. Yet these processes do not occur independently; rather, metal–protein interactions, protein aggregation, ROS generation, and other disease-associated pathways form interconnected molecular networks whose individual contributions can be difficult to distinguish using conventional biological approaches.

The Lim Laboratory designs small molecules as chemical tools to identify, interrogate, and selectively manipulate these complex networks. Through rational control of molecular structure, metal coordination, recognition, and chemical reactivity, we develop molecules capable of targeting metal ions, metal-bound amyloidogenic proteins, ROS, and related pathological species. These chemical tools enable us not only to modulate aggregation and oxidative pathways but also to uncover the molecular mechanisms through which individual and interconnected pathological factors contribute to neurodegeneration.

Project III: Multi-Target Chemical Modulators for Pathological Network Regulation

The pathogenesis of neurodegenerative diseases involves multiple interacting factors rather than a single molecular target. These include metal dyshomeostasis, protein misfolding and aggregation, oxidative stress, neuroinflammation, and dysregulated enzymatic and signaling pathways. Consequently, selectively controlling only one pathological component may be insufficient to effectively regulate such multifactorial disease processes.

To address this complexity, the Lim Laboratory develops single-molecule platforms capable of interacting with and regulating multiple pathological factors. Rather than simply combining independent pharmacophores, we seek to understand how molecular structure and chemical reactivity can be programmed to produce coordinated activities toward interconnected disease-associated targets. This approach establishes chemical principles for multi-target modulation of pathological networks and provides molecular platforms with potential applications in diagnosis and therapy.

Project IV: Bioinspired Metal Complexes and Redox Chemistry for Controlling Oxidative Stress

Reactive oxygen species are essential components of biological redox signaling but can become highly damaging when their production and removal are dysregulated. Metalloenzymes naturally control these reactive species through precisely orchestrated metal coordination, electron transfer, and substrate activation. Understanding these fundamental reactions provides an opportunity to reproduce and manipulate such chemistry using synthetic systems.

Inspired by metalloenzymes such as catalase, the Lim Laboratory investigates the fundamental reactivity of synthetic metal complexes, including high-valent metal–oxo species, toward biologically relevant oxidants such as H₂O₂. We use mechanistic inorganic chemistry to determine how metal identity, coordination environment, and ligand structure govern redox reactivity. These studies provide fundamental insight into biological metal-mediated oxidation chemistry and guide the development of bioinspired molecular systems capable of controlling oxidative stress in complex biological environments.