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Pilot Project Awardees

2020-2021 Awards

David Assis, MD

Associate Professor, Internal Medicine: Digestive Diseases

Project Title: A pilot study of a novel bacteriophage approach to target pathogenic gut-derived bacteria in patients with Primary Sclerosing Cholangitis

Primary Sclerosing Cholangitis (PSC) is a devastating, progressive, autoimmune cholangiopathy without any effective treatment, frequently characterized by concurrent inflammatory bowel disease. The critical role of pathogenic bacterial species in the gut microbiome of PSC patients has been increasingly recognized. It has also been recognized that some pathogenic gut bacteria, including toxigenic Klebsiella pneumoniae, are especially pathogenic and can cause direct liver damage in PSC. However, there are several potential limitations to treating the PSC microbiome with broad-based, long-term antibiotics. Viral Bacteriophage technology has significantly advanced in recent years and is applied to an increasing number of human diseases, demonstrating exquisite specificity for selectively eliminating pathogenic bacteria. However, the application of bacteriophage technology to human PSC has only recently been considered. This pilot project will unite expertise from the Yale Liver Center and the Yale Center for Bacteriophage Research and Therapy to perform a novel investigation into the role of bacteriophages in the modulation of the microbiome using stool from patients with PSC, bacteriophages specifically targeting pathogenic Klebsiella pneumoniae, and the effect of this therapy on the reactive inflammatory phenotype of cholangiocytes in PSC using the human bile-derived organoid model. This project will allow us the opportunity to gain critical insight into the ability of bacteriophages to be considered as a new therapeutic option for patients with PSC.

Michael Mak, PhD

Assistant Professor, Biomedical Imaging

Project Title: Mechanobiology-Driven Heterogeneity and Therapeutic Resistance in Liver Cancer

As liver tumors expand in confined and often stiff and fibrotic tissue environments, they can become highly compressed, triggering mechanotransduction events. Our overall goal is to investigate how this mechanical stimulation impacts the evolution of liver tumors. In particular, we will characterize heterogeneity in mechanobiological phenotypes and differential responses to therapeutics. We will further investigate the mechanics-induced emergence of treatment resistant cells.

Matthew McConnell, MD

Instructor of Medicine, Internal Medicine: Digestive Diseases

Project Title: The Role of Platelets in the Pathogenesis of Alcohol-Related Hepatitis

Thrombosis and hemostasis in liver disease remain poorly understood. While platelets and microvascular thrombosis within the liver are recognized as drivers of liver disease pathogenesis, how specific hemostatic alterations contribute to the progression of liver disease remains incompletely defined. Alcohol is at the intersection of platelet biology and liver disease, being both a common cause of cirrhosis while also having direct pathological effects on the bone marrow and platelets themselves. The goal of this study is to define the role of platelets, the key hemostatic cells of the body, in driving progression of alcohol-associated hepatitis through their interactions with liver sinusoidal endothelial cells. Completion of this project has the potential to define a new paradigm of therapy in alcohol-associated hepatitis.

Silvia Vilarinho, MD

Assistant Professor, Internal Medicine: Digestive Diseases; Pathology

Project Title: mRNA-based therapeutics for liver disease: a pilot study

Chronic liver disease represents a major health problem, accounting for over 120 million cases of end-stage liver disease (ESLD) worldwide. The only curative intervention available for patients with ESLD is liver transplantation, and its demand far exceeds the supply of available donor organs. Hence, non-invasive medical therapies are an unmet medical need. Our research group has identified that liver homeostasis is compromised when liver endothelial cells lack expression of Gimap5, a small GTPase. Specifically, we discovered that the absence of Gimap5 leads to a near complete replacement of liver sinusoidal endothelial cells (LSECs) by capillarized endothelial cells (CECs). In this proposal, we plan to test whether restoring Gimap5 protein expression using lipid nanoparticle based Gimap5 mRNA delivery will revert CECs into a healthy state and may have a therapeutic effect in the Gimap5 loss-of-function mutant mouse model.

Publication Acknowledgment

To cite the Liver Center in your publications please use the following statement:

”This project was supported in part by the Yale Liver Center award NIH P30 DK034989 ________ core.”
(insert name of core(s) that you used-Morphology, Cellular Molecular, Clinical-Translational)