Projects

Project I: Identification of Metal-Directed Interactions and Reactivities among Multiple Elements at the Molecular Level in Dementia

Multiple components, including metal ions, proteins, neurotransmitters, and mediators for oxidative stress and inflammation, are suggested to be inter-communicated with each other and linked to the pathogenesis of dementia, including AD and PD. In particular, metal ions are observed to interact and react with pathogenic peptides and proteins, reactive oxygen species (ROS), and/or other species, which could facilitate the pathology or protect cells against toxicity-related pathways. Until now, however, our molecular-level understanding of the metal-involved networks composed of proteins, neurotransmitters, and mediators for oxidative stress and inflammation is very limited. In addition, how such networks are associated with neurotoxicity leading to dementia has not been revealed. To determine how metal-involved biological networks composed of proteins, neurotransmitters, and mediators for oxidative stress and inflammation are linked to dementia, Lim lab has been investigating metal-directed interactions and reactivities among these multiple features at the molecular level by multidisciplinary approaches (i.e., bioinorganic, biochemical, biophysical, and biological studies).

Project II: Design of Small Molecules as Chemical Tools Targeting and Modulating Individual and Inter-related Metal-linked Pathological Factors in Dementia

A distinct feature of AD and PD is the accumulation of misfolded proteins (e.g., for AD, aggregates of amyloid-β (Aβ) or hyperphosphorylated tau). Some in vitro and in vivo studies have suggested that the interactions between metal ions and misfolded proteins could be related to disease development, along with ROS generated by metals and metal-associated misfolded proteins (metal-misfolded proteins). This relationship among metal-misfolded proteins, ROS, and pathogenesis has not been clearly revealed, however. To gain a greater understanding of this relation, Lim lab has been focusing on designing small molecules as chemical tools that can target specifically metal-misfolded proteins, modulate their interactions, and eventually alter their reactivity (i.e., aggregation, ROS production). In addition, some of these chemical tools can also serve as antioxidants. Lim lab has recently prepared and characterized several series of small molecules capable of specifically targeting metal–Aβ complexes and subsequently diminishing metal–Aβ toxicity in vitro, in living cells, and in vivo (transgenic mouse model of AD).

Projects III & IV: Development of Small Molecules or Metal Complexes as Potential Therapeutics Targeting Multiple Pathological Facets in Dementia

In dementia, multiple factors and processes are suggested to be involved in pathogenesis. These pathological elements include enzymes [e.g., acetylcholinesterase (AChE) for AD, monoamine oxidase B (MAOB) for PD] and ROS, along with metals and misfolded proteins (see Program II).

Project III: In order to discover effective therapeutics for devastating brain disorders (e.g., AD and PD), Lim lab has been taking an innovative approach to designing a single molecule targeting and subsequently regulating multiple pathological factors [i.e., metal ions, misfolded proteins, ROS, and enzymes (AChE or MAOB)]. Due to complicated, interconnected pathogenesis in dementia, an effective drug for multiple targets would be desirable.

Project IV: In cellular antioxidant defense systems, catalase acts as an enzymatic scavenger of H₂O₂ converting it to dioxygen and water. To clarify the mechanism of H₂O₂ decomposition by catalase, which is believed to involve a high-valent metal-oxo intermediate, Lim lab has been investigating the reactivity of synthetic oxoiron species with H₂O₂. Based on these studies and inspired by the structure and function of catalase, Lim lab will construct efficient detoxifiers of H₂O₂ in biological systems.