Lithium salts have been used to treat severe bipolar disorder and major depression for decades, especially in instances with high suicide risk, and lithium remains their most effective treatment today. Despite its efficacy, lithium's therapeutic window is narrow, since it is difficult to maintain an effective concentration in the body without incurring severely detrimental side effects. This proposal aims to use metal-organic frameworks, a crystalline and porous class of hybrid organic-inorganic materials, for the slow and extended release of lithium as a therapeutic treatment for mood disorders. Metal-organic frameworks, as robust, tunable, and structurally well-defined materials, offer the advantages of facile modification and characterization. Through judicious choice of metals nodes, organic linkers, and guest species it will be possible to tune the thermodynamics and kinetics of Li+ uptake and release. Strategies for lithium interaction will include appending small organic molecules to open metal coordination sites, incorporating lithium-binding functional groups onto the backbones of organic linkers, and post-synthetically exchanging lithium for framework cations while maintaining crystallinity. Potential frameworks of interest will be synthesized using standard organic and inorganic synthesis methods and then subjected to a diverse toolbox of characterization techniques including: powder and single-crystal X-ray diffraction, gas sorption measurements, solution and solid-state NMR spectroscopy, and multiple forms of elemental analysis. Lithium uptake and release will be monitored via solution-state isotherms and kinetic measurements as well as by crystallographic and spectroscopy analysis of the frameworks in their (de)lithiated states. Promising materials will be iteratively improved and subjected to simulated biological conditions for the release of lithium. If successful, this project will position metal-organic frameworks as a versatile platform for addressing the important health challenge of treating severe neurological disorders with lithium. This research will take place in a supportive environment centered within a lab group that has a wealth of expertise in the synthesis and characterization of porous materials. The research will be assisted by a host of long-standing industrial, academic, and national lab collaborations. In addition to significant training in experimental techniques, this project will include guidance toward an academic faculty career, training in responsible conduct of research, professional development through interaction with scientific colleagues, and opportunities for mentorship of other students and researchers.

Public Health Relevance

Lithium carbonate is the current state-of-the-art treatment for bipolar disorder and other neurological disorders, especially in cases of high suicidality, and yet it is beholden to a narrow therapeutic window bordered by inefficacy in low concentrations and dangerous side effects in high concentrations. This proposed project aims to develop effective new materials for the controlled and extended release of lithium for therapeutic applications as well as to study the fundamental interactions between lithium and the modular components of these materials.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Bond, Michelle Rueffer
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University of California Berkeley
Schools of Arts and Sciences
United States
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