Congratulations to the Pilot and Feasibility Awardees for the 2016-2017 cycle:


Moses Bility, PhD

Moses Bility – Department of Infectious Diseases and Microbiology
Nonalcoholic fatty liver disease (NAFLD) is a major cause of morbidity and mortality in the developed world, and the incidence of NAFLD is rapidly increasing in developing countries (1). There are no effective therapies for treating NAFLD (1). The underlying pathogenic mechanisms by which fatty diet promotes chronic liver inflammation and fibrosis remains unclear, due in part to the lack of robust small animal models. We recently developed novel humanized mouse models carrying autologous human liver and immune system cells that recapitulates human inflammatory liver diseases (2-5). In preliminary studies, using this humanized mouse model along with clinical samples, we demonstrate that nonalcoholic fatty liver and associated chronic liver inflammation in both humanized mice and humans is characterized by high levels of M2-like polarized macrophages. This finding is supported by the known critical role that macrophages play in modulating host response and tissue pathology (6). Indeed, M2-like monocyte/macrophage activation has recently emerged as a prominent feature in many human liver diseases including Nonalcoholic steatohepatitis (NASH) (7-9). Our central hypothesize is that fatty diet induces liver inflammation and fibrosis via gut microbiota-induced M2-like macrophage activation in the liver.

Bryan Brown, PhD

Bryan Brown – MIRM/ Department of Bioengineering
In the United States alone, 30 million individuals suffer from chronic liver disease, with increased severity and poor prognosis in the elderly population. By 2050, the number of individuals living to be 65 or older is expected to increase by 71%, resulting in a global aging crisis. Age-related changes in hepatocyte function have been
well-characterized, but the effects of aging on non-parenchymal liver cells and consequences for the health of the host are virtually unknown. Kupffer cells (KCs), liver-resident macrophages, are primarily responsible for inducing tolerance to gut bacterial products delivered from the portal circulation by producing IL-10 in response to low-levels of LPS. With high levels of LPS and additional danger signals, KCs are activated, produce inflammatory cytokines, and efficiently clear bacteria by phagocytosis. With advanced age, the number and activation of Kupffer cells has been reported to increase, suggesting a breakdown in the tolerance of the immune system to gut-derived signals and perhaps contributing to increased systemic inflammation that has been termed “inflamm-aging” and is hypothesized to exacerbate many age-related pathologies. We hypothesize that increased activation of liver-resident macrophages with aging is due to 1) a shift in the ontogeny of macrophages from embryonic derived to bone marrow derived cells and 2) increased stiffness and altered bioactivity of the extracellular matrix composing the macrophage niche.

Qingde Wang, MD, PhD

Qingde Wang – Department of Surgery
Nonalcoholic steatohepatitis (NASH) is an advanced form of Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease. NASH is one of the leading causes of cirrhosis that may progress to liver failure and/or hepatocellular carcinoma, forms a major challenge to public health. The hallmarks of NASH is inflammation occurrence, which distinguishes NASH from the simple steatosis (fatty liver). Despite the clinical significance of inflammation in NASH, the underlying mechanism by which the inflammation is triggered remains poorly understood, hindering the development of an effective treatment for this disease. Recently we found that the RNA editing enzyme adenosine deaminase acting on RNA1 (ADAR1) plays a critical role in activation of innate immune system through cytosolic RNA sensing pathway, and plays an important role in sterile inflammation. In addition, we demonstrated that ADAR1 is essential in protecting liver from inflammation injuries. Specifically, we showed that ADAR1 suppresses endogenous “self” RNAs to elicit an inflammatory reaction in liver, whereas liver-specific knockout of ADAR1 caused liver pathogenesis showing the characteristics of NASH, including lipid accumulation, inflammation, hepatocyte damage and fibrosis. Our data supports a hypothesis that RNA editing enzyme ADAR1plays a critical role in NASH through activating the innate immune RNA sensing signaling pathway and elicits inflammation, and consequently promoting the transition from steatosis to NASH.

Alex Soto-Guteirrez James Squires, MD, M

Alex Soto-Guteirrez (Department of Pathology) & Jim Squires (Department of Pediatrics)
The hepatocyte canalicular membrane serves as the gateway through which bile acids, phosphatidylcholine, cholesterol, xenobiotics, and other by-products of hepatocyte metabolism must pass to form bile. Disruption of canalicular function, therefore, is expected to have detrimental effects on liver and human health. A number of autosomal recessive disorders are known to disrupt hepatocyte canalicular function and bile secretion. Progressive familial intrahepatic cholestasis (PFIC) is a group of rare diseases clinically manifested by intrahepatic cholestasis in children and progresses to end stage liver disease and death or liver transplantation. Two PFIC disorders, PFIC 1 and 2, have been described based on clinical phenotype, specific genetic abnormalities, and a distinctively low level of serum gamma glutamyltransferase (GGT); they are referred to collectively as low-GGT PFIC. Mutations in ATP8B1 (PFIC1) and ABCB11 (PFIC2) result in dysfunctional or absent Familial Intrahepatic Cholestasis 1 (FIC1) protein and the bile salt exporter pump (BSEP), respectively. Both FIC1 protein and BSEP are critical to canalicular membrane function. We intend to initiate a unique collaboration between clinical, basic, and translational scientists to investigate perturbations of hepatocyte canalicular function that develops in patients with low-GGT PFIC.

Clinical-Translational Award

Michael Dunn, MD Christopher Hughes, MD

Michael Dunn (Department of Medicine) & Chris Hughes (Department of Surgery)
Muscle wasting with the loss of capacity to withstand physical stress is now well known as a key barrier to the ability of waitlisted patients to survive and recover from liver transplantation. National data show that 20 percent of candidates are removed from waitlisting for deterioration when the metabolic, nutritional and infectious complications of cirrhosis cause their physical stamina to fall below what could be expected to support recovering from a transplant. It is now clear that this lethal and prevalent adverse event is strongly associated with and predicted by measured anatomic loss of muscle mass on imaging, termed sarcopenia, and by deteriorating performance on physical testing such as gait speed or six-minute walk distance. A unifying concept in chronic disease management, frailty, defines a common phenotype of physical decline with heightened vulnerability to the stresses of advanced chronic diseases such as cirrhosis. As waiting list times lengthen due to the donor organ shortage, most waitlisted patients experience physical decline as their Model for Endstage Liver Disease (MELD) scores rise. The challenge for transplant centers is keeping patients healthy enough, at a high MELD score, to still receive a transplant. In 2015, 1419 listed patients died while waiting for a liver, while another 1473 were removed because they became too sick for transplant to remain an option. More and more we are seeing that debility and physical decline, rather than sudden acute illness, is the reason the option is taken away. Our proposal is designed to maintain health and help prevent delisting for physical decline by sustaining the physical performance that appears to protect patients from progression of frailty.