Co-Clinical imaging research.
Multi-disciplinary effort to facilitate the promise of precision medicine by optimizing the use imaging and realistic animal models of cancer (e.g., PDX, GEMM) to better inform of therapeutic outcome in clinical trials. The overall goal of the project is to develop and implement advanced quantitative imaging (QI)/radiomic pipelines to predict response to therapy in TNBC, and integrate to QI/radiomic image features with multi-scale analytic data (-OMICS, path) via machine learning algorithms to enhance prediction. Please visit https://c2ir2.wustl.edu/ for more details.
Systems imaging: Multi-tissue, multi-tracer metabolic phenotyping of diabetes
Type-2-Diabetes (T2D) is a result of systemic disturbances in metabolism characterized mainly by impaired insulin action in peripheral tissues such as liver, muscle, and adipose tissue as well as central coordination the the central nervous system. In light of the highly interconnected and coordinated nature of substrate metabolism in health, and its failure in T2D, current research necessitates an integrated in-vivo systems imaging strategy to investigate multi-tissue metabolic alterations in the etiology of insulin resistance in obesity and diabetes. The goal of this proposal is to elucidate imaging biomakers for the progression of diabetes using pre-clinical animal models of diabetes. In addition, we develop and validate computational models to quantify metabolism in liver, muscle, brain, and adipose tissue in-vivo.
Gender-differences in diabetic heart disease
Cardiovascular disease is the leading cause of death in these patients with with atherosclerosis accounting for approximately 80% of the cases. However, there increasing evidence for a true diabetic cardiomyopathy — the presence of left ventricular hypertrophy with systolic and diastolic dysfunction that occurs in the absence of concomitant coronary artery disease. Of note, the cardiovascular manifestations of T2DM are more pronounced in women as compared with men, with female gender portending a greater likelihood of developing heart failure and an overall poorer prognosis either when heart failure occurs de novo or following myocardial infarction. Overdependence on FA metabolism and a decrease in glucose use typifies the metabolic phenotype in T2DM. The increase in plasma FA delivery due to peripheral insulin resistance leads to increased myocardial FA uptake which activates key transcriptional pathways such as the PPARa/PGC-1 signaling network resulting in further myocardial FA utilization and oxidation. The goal of this project is to elucidate the role of gender in the interplay between fatty acid metabolism, oxidative stress, and diabetic cardiomyopathy.
PET imaging of oxidative stress in T2DM
Reactive oxygen species (ROS) are important mediators in the pathogenesis of a wide range of diseases such as cancer, neurocognitive and neurodenerative disorders, and diabetes mellitus. Moreover, oxidative stress secondary to increased ROS is central to pathogenesis various cardiovascular diseases including arteriosclerosis, hypertension, and heart failure. ROS include the free radical superoxide anion (O2-), hydroxyl radical (OH-), and hydrogen peroxide (H2O2). O2- and OH- are highly reactive while H2O2 is significantly more stable. O2- can rapidly react with nitric oxide (NO-) to form peroxynitrite (ONOO-), which can inflict further structural damage through lipid peroxidation. A common theme to the reactions is that superoxide initiates the cascade of ROSs. There are several cellular defense mechanisms that counter balance the production of ROS, including the catalase and glutathione perxidase as well as superoxide dismutase (SOD). Catalase and glutathione perxidase catalyze the conversion of H2O2 to water while SODs eliminate O2- through the formation of the more stable of H2O2. In pathophysiological states, increased ROS production beyond cellular defensive mechanisms damages the mitochondria and ultimately results in more ROS production creating a viscous cycle in which ROS will interact with DNA causing mutations, proteins causing defects or dysfunctional enzymes, and lipids causing damage to cellular membranes. In collaboration with the lab of Dr. Robert Mach, we are working on validating PET radiopharmaceuticals of superoxide load using pre-clinical animal models. Of particular interest, is application of imaging ROS load in diabetic cardiovascular disease.
Ex-vivo artificial tissue bioreactor
An artificial tissue bioreactor is a versatile system designed to simulate the 3-dimensional (3D) structure and microenvironment of tissues in vivo. In vivo, the responses of individual cells are regulated by spatiotemporal cues that reside in the local microenvironment such as the extracellular matrix (ECM), neighboring cells, soluble factors and physical forces, all presented in a 3D context. When cells are isolated from their in-vivo environment, they are usually placed in a monolayer environment with limited cell-cell contact and bathed in a static medium, thus spatiotemporal cues are lost resulting in a multitude of cells displaying phenotypic instability. We are currently developing a mobile artificial tissue bioreactor to be integrated with imaging instruments to facilitate research, discovery, and validation of therapeutic and imaging biomarkers.