Multiscale Control of Liver Repair & Regeneration
How does liver regenerate? Which control aspects of liver repair go awry in disease? How to stimulate robust tissue regeneration after liver surgery? Can we predict the temporal progression of the regeneration outcome following a suboptimal liver transplant?
Liver regeneration is a clinically important tissue repair process, which involves an interplay of coordinated signals from different cell types integrated with the systemic factors to recover functional tissue mass. Despite decades of research and the recognition of several molecular components that facilitate or impair the regeneration response in rodents, an effective mechanistic understanding of the factors that drive the temporal progression and coordinate the tissue repair responses across different cell types, has remained elusive. We pursue a systems biology strategy that combines multiscale network modeling with the functional genomics data sets at the single cell scale to fill this major gap in our knowledge. Recently, we developed a novel computational model to account for various cellular and molecular aspects of liver regeneration following partial hepatectomy. Our modeling studies provide new insights into how the dynamic state transitions of multiple cell types are integrated towards a coordinated control of the liver regeneration process. We are translating the network model to the human condition to support clinical decision-making in the liver surgery and transplant scenarios.
Alcoholic Liver Disease & Transcriptional Regulatory Networks Driving Repair
How does chronic alcohol consumption disrupt liver regeneration? How to counter ethanol-induced suppression of liver repair?
Chronic alcohol intake is detrimental for the regenerative response of liver. The impaired regeneration response may increase susceptibility to persistent liver damage after acute liver injury in alcohol-dependent individuals and thereby contribute to the onset of chronic liver disease. A better understanding of the mechanistic basis of this impairment has clinical implications for a wide range of ethanol-induced liver defects. Our transcriptomics and genome-wide transcription factor binding studies thus far provided strong evidence that ethanol affects interactions between hepatocytes and non-parenchymal cells that are essential for a coordinated and integrated repair response. Our single cell gene expression studies revealed, for the first time, that chronic ethanol consumption shifts the proportions of hepatic stellate cells across a defined set of molecular states, with consequences on the overall tissue response to injury. We are presently testing the efficacy of microRNA-based interventions for resetting the distribution of hepatic stellate cell molecular states to rescue from ethanol-induced deficiencies in liver regeneration.
Neuroinflammation, Neuroimmune Processes, Hypertension & Heart Failure
How do the intracellular processes and cell-cell interactions in the brainstem circuits evolve during the development of hypertension and in heart failure? Which regulatory mechanisms are maladaptive? Which control points should be manipulated for prevention and rescue?
Hypertension is a major chronic disease worldwide; one third of the population in the United States is hypertensive, and alarmingly, nearly half of the individuals using anti-hypertensive medication do not have their blood pressure well controlled. These patients exhibit autonomic dysregulation and are susceptible to heart failure. It is now compelling that neural contributions to hypertension are a major cause in the development of essential hypertension, due to amplified angiotensin II signaling and specific neuroinflammation. Our efforts are focused on identifying molecular, cellular and circuit mechanisms that are essential for robust control of blood pressure and cardioprotection. Our single cell scale experiments and multiscale modeling studies uncovered extensive plasticity and remodeling of brainstem autonomic control circuits in response to physiological perturbations as well as during the development of hypertension. We are pursuing computational modeling and experimental studies on microRNA-mediated regulation of inflammation, immune response and signaling processes to interfere with the development and maintenance of hypertension, as well as enhance cardioprotection for preventing heart failure.
Cell Fate Regulation Underlying Developmental Defects
What are the limits of the homeostatic robustness of cell fate regulation in the early embryo? How do the intra- and inter-cellular feedback control loops contribute to the coordinated progression of multiple lineages? What are the effective control points to manipulate in order to prevent or rescue from developmental defects?
Formation of functional tissues and organs during development relies on a coordinated progression of different cell lineages. This coordination is partly achieved by interplay of intra- and inter-cellular regulatory networks that confer some level of robustness to perturbations. There is limited knowledge on the homeostatic feedback mechanisms regulating cell fate in the early differentiation, and how these controls are disrupted by genetic and environmental factors in leading to developmental defects. Our collaborative studies are focused on the defects in the development of the brain and the cardiovascular system. We showed, for the first time, that ethanol exposure diverts the progression away from neural lineage due to a shift in the balance of key regulators (Oct4 versus Sox2) in individual cells. We are presently testing microRNA-based interventions to reverse ethanol-induced shifts in early lineage progression. Ongoing studies are yielding novel findings on the regulatory modules underlying neuroectodermal and cardiac mesodermal lineage progression.