Our goal is to develop small molecules that modulate cardiometabolic disease-associated genes.
To achieve this objective, our lab focuses on the following activities: genetic discovery in human cohorts, genome editing in zebrafish and human cell lines, mass spectrometry-based metabolite profiling, and high throughput screening using small molecule libraries. We apply these approaches to the following ongoing projects.
Illuminating the function of the understudied "druggable" kinome using human phenotypes and model organisms
Kinases are enzymes that regulate every aspect of cellular activity. Despite the widely recognized importance of kinases in human biology, a significant portion of the human kinome remains poorly characterized. Assigning functions to the remaining understudied kinases would reveal many new insights into human biology and have a transformative effect on human health. We systematically identify connections between these understudied kinases and the human biology they regulate through the integration of genomics, proteomics and metabolomics data. Using genome editing and high throughput screening approaches in zebrafish and human cell lines we further dissect the molecular mechanisms of these functional associations.
Genetic and small molecule elucidation of cardiometabolic diseases
By building discovery pipelines that utilize biochemical and ‘omics approaches, we interrogate the fundamental pathways of cardiometabolic diseases. The overarching goal of these studies is to understand disease evolution. Further, we utilize the tools of chemistry and chemical biology in combination with genetic models in zebrafish to identify novel therapeutic targets. For example, we developed a high-throughput drug screening platform for energy homeostasis in zebrafish. Through this screen, we identified phosphorylated succinate dehydrogenase (SDH) as a novel substrate of the phosphatase PTPMT1. Establishing a link between PTPMT1 and SDH not only ascribed a new function to a poorly understood phosphatase (PTPMT1) but also revealed a novel molecular regulatory mechanism for SDH, an enzyme that is essential for mitochondrial function and the coordinated utilization of glucose.
Drug discovery and preclinical studies that meet FDA definition of readiness for advanced development
We are part of a consortium seeking to develop a deployable cyanide antidote for mass causality incidents. Our lab developed a series of high throughput chemical screens. These scalable assays monitor a wide range of morphological, physiological, molecular and behavioral phenotypes including glucose homeostasis, mitochondrial potential, cardiotoxicity, neurotoxicity and survival in zebrafish. To optimize potency and toxicity of hit compounds, we perform structure-activity relationship studies to elucidate the physicochemical features, ligands, and formulations that influence their efficacy and safety. From these studies, a lead compound emerged, which exhibits efficacy in zebrafish, mice, rabbits, and pigs. Currently, this compound is being optimized to meet the formal requirements for advanced development and clinical deployment.
Mechanisms of metabolic poisoning and rescue
Cyanide is the prototypic mitochondrial poison. Identifying the broad spectrum of metabolic derangements secondary to cyanide toxicity may highlight pathways for therapeutic intervention for a range of metabolic poisons. The overarching goal of these metabolic studies is to explore how metabolism can be redirected to mitigate the effect of potent metabolic poisons. These discoveries pave the way for development of therapies that are fundamentally different from existing therapeutics and have the potential to transform our ability to respond to metabolic poisons. This project leverages the mass spectrometry facility in our department which houses four LC-MS metabolomics platforms.
SNP to function: Building a compendium of gene-analyte associations
The mechanism by which gene-disease or gene-trait associations contribute to the disease process are often unclear. Therefore, integration of complementary methods is required to frame these genes into molecular pathways and to begin to understand the mechanisms by which they contribute to human physiology. To bridge this gap, our group has generated unique human datasets that integrate human genetic variation with proteomics and metabolomics data (~5,000 analytes) to begin to map the genetic architecture of the human metabolome and proteome. We are leveraging our compendium of gene-analyte associations to determine metabolite or protein profiles “downstream” of genetic variants.