UCLA

The integration of basic biological research and contemporary drug discovery and development strategies stands at the forefront of scientific efforts to develop treatments for innumerable medical conditions. Advances in genomics, molecular biology, computer science and 'omics' technologies have enabled a holistic understanding of complex disease mechanisms, facilitating the identification of novel biomarkers and therapeutic targets. Modern pharmaceutical research tools have led to a well-established drug discovery workflow that often drives efforts to efficiently develop safe and effective therapeutics. This approach typically involves the use of high-throughput screening to identify “hits” that achieve a desired phenotype. This is followed by an optimization process utilizing in-vitro ADME assays and medicinal chemistry to develop more selective, potent, and bioavailable compounds. Finally, in-vivo testing in disease-relevant models allows for proper evaluation of drug efficacy before moving into preclinical or clinical development. This dissertation focuses on the use of these approaches in the context of drug discovery programs targeting innovative therapeutic mechanisms such as increasing secreted clusterin for Alzheimer’s disease, inhibiting microtubule affinity-regulating kinase 4 for vascular cognitive impairment, enhancing calcium calmodulin II kinase signaling for limb-girdle muscular dystrophy, and increasing sarcospan for Duchenne muscular dystrophy. Leveraging advanced scientific tools, the research explores the intricate mechanisms underlying these diseases and identifies promising new drug candidates and therapeutic approaches that warrant further investigation as disease treatments.