MAJOR AREAS OF RESEARCH
Aging, Fibroblast Senescence, and Apoptosis in Lung Fibrosis:
Fibrosis or ''scarring'' of vital internal organs is an increasing cause of debilitation and death worldwide. Human fibrotic disorders affect many organ systems including the heart, blood vessels, skin, kidney, liver, and lungs. ~45% of deaths in the U.S. are attributed to disorders that are characterized by varying degrees of fibrosis. This alarming statistic is often underappreciated since the “cause of death” is often end-stage organ failure; however, organ failure is predominantly attributed to progressive fibrosis. There is a growing ''epidemic'' of fibrotic disorders among the aging population. The most severe fibrotic lung disease is idiopathic pulmonary fibrosis (IPF), a relentlessly progressive and fatal disorder that primarily affects the elderly population.
Dr. Hecker was the first to define a novel role for the oxidant-generating enzyme, NADPH oxidase-4 (Nox4), in mediating pro-fibrotic myofibroblast functions and tissue fibrosis (Nature Medicine, 2009). Since this initial discovery that Nox4 mediates lung fibrosis, Nox4 has been implicated in fibrosis of various organ systems, including the kidney, liver, skin, and heart. Nox4 is now considered to be among the most promising targets for fibrotic disease. Dr. Hecker has also developed a novel aging mouse model of non-resolving lung fibrosis, which more accurately reflects the persistent/progressive nature of human fibrotic lung disease. Using this model, we have demonstrated that lung injury leads to the acquisition of a senescent and apoptosis-resistant myofibroblast phenotype in aged mice, which impairs fibrosis resolution. Further, this myofibroblast phenotype is mediated by a redox imbalance associated with sustained activation of Nox4 (a major source of oxidant generation) and deficient activation of Nrf2 (a master regulator of the antioxidant response) (Science Translational Medicine, 2014).
The impact of these findings is that it challenges the existing paradigm that pathological fibrosis is a “fibro-proliferative” process. Instead, we propose that myofibroblast senescence and apoptosis-resistance (failure to undergo cell death) leads to the accumulation of myofibroblasts in fibrotic disorders. This previously unknown pro-fibrotic mechanism may help explain the propensity of fibrotic disorders among the elderly population and offer novel insights for the development of therapeutic interventions aimed to treat age-associated fibrotic diseases. Current research efforts in the Hecker lab are focused on understanding the cellular and molecular mechanisms that mediate these age-dependent pro-fibrotic phenotypes.
Pre-clinical development of novel drug candidates for age-associated lung disease:
To date, no drug treatment has been shown to improve quality of life for IPF patients. Better treatments for IPF and other fibrotic diseases are sorely needed. Although Nox4 is considered to be among the most promising targets for fibrotic disease, no selective Nox4 inhibitors are clinically available. Over the past 10 years, Dr. Hecker has pioneered Nox4 discovery and pre-clinical development efforts. Using a high through-put screening (HTS) approach, >30,000 compounds were screened, which led to the identification of several “hits” as potential Nox4 inhibitor candidates. With the help of medicinal chemistry efforts, we have successfully identified 2 distinct compound series that are highly selective and effective for Nox4, with favorable pharmacokinetic/pharmacodynamic properties. The major goal of our current efforts is to deliver a therapeutic product that demonstrates efficacy in the most rigorous animal models and a favorable toxicology profile, which is ready to advance into good laboratory practice (GLP)-IND enabling toxicity studies (required for Phase I human clinical trials). To accomplish these goals, we are working with a number of collaborators that assist with various aspects of the project including, medicinal chemistry, pharmacology/toxicology, and target engagement. We have also partnered with Lovelace Respiratory Research Institute, the nation’s leading contract research organization specializing in respiratory therapeutic development.
In addition to the development of Nox4 inhibitors for fibrotic disease, the Hecker lab is also developing these drug candidates for Acute Respiratory Distress Syndrome (ARDS). The Hecker lab also has several other ongoing platforms to develop novel therapeutics, including drug re-purposing, novel formulation development, and evaluating novel mechanisms of FDA-approved therapeutics.
Age-related mechanisms contributing to susceptibility of Acute Lung Injury:
Acute respiratory distress syndrome (ARDS) is a devastating critical illness that disproportionately affects the elderly population. We recently developed a novel two-hit preclinical model of acute lung injury (ALI), which was used to evaluate reparative responses to lung injury in young vs. aged mice. We found that aged mice exhibit significantly increased severity of ALI, associated with impaired vascular barrier-regulatory responses and elevated expression of Nox4. Since the integrity of the lung endothelial cell (EC) monolayer is critical for preservation of lung barrier function, they sought to determine if senescence alters EC permeability responses. Indeed, senescent ECs exhibit exacerbated permeability responses, mediated by sustained expression Nox4. Further, we found that Nox4 expression was rapidly regulated via post-translational regulation by the proteasome-ubiquitin pathway, which is dysregulated in aging. These studies provide novel insight into the role of Nox4/senescence in regulating EC barrier responses and offer a mechanistic link to the increased incidence/mortality of ARDS in aging. Ongoing efforts are focused on the continued validation of the role of Nox4 and its splice variant, Nox4D, in maintaining EC integrity during acute responses to lung injury.
Another project in the acute-injury arena is focused on sepsis-related multiple organ dysfunction syndrome, a leading cause of death in intensive care units. Overwhelming evidence implicates oxidative stress in the pathogenesis of sepsis-associated multiple organ failure, yet there are no ROS–associated biomarkers and/or predictive diagnostics. Using genetic approaches and Dr. Hecker’s knowledge of ROS-genes associated with disease, we have identified a 21-gene ROS-associated molecular signature that predicts survival in septic patients. Importantly, this signature was validated at two different hospital sites with distinct patient populations. We are currently seeking industry partnerships interested in developing this technology as a prognostic tool, which could facilitate the development of personalized therapies.