Research/Projects
Advances in genomic and proteomic technologies, along with bioinformatic tools, have greatly improved our ability to generate and process large-scale biological datasets from human samples. These high-throughput "-omics" data have expanded our understanding of the human genome, transcriptome, and proteome, offering revolutionary insights into human biology and disease. However, the application of these advancements to gain mechanistic insights into diseases and establish causality through controlled perturbations (genetic or chemical) remains limited.
At the Sefik Laboratory, we model and mechanistically study human infectious, inflammatory, fibrotic diseases, and cancer. We combine in vitro and in vivo models, bioinformatic approaches, and perturbation studies in humanized mice to examine the role of various human immune cells in disease pathophysiology. These humanized mice are reengineered to express physiological factors that enable the development of most human hematopoietic cells. By humanizing factors such as M-CSF (monocytes, tissue macrophages), GM-CSF/IL-3 (lung alveolar macrophages), THPO (hematopoiesis and platelets), SIRPA (macrophage tolerance to human cells), and IL-6 (enhanced hematopoiesis and inflammatory responses), we created MISTRG6 (an acronym for the genes replaced) mice.
The MISTRG6 system offers many advantages over other humanized mouse models, particularly in the levels and distribution of myeloid cells, which are heavily involved in chronic inflammatory diseases affecting peripheral tissues. Additionally, we utilize humanized organ systems, primarily liver and lung, which accurately model the interactions between human immune and non-immune cells, providing unique opportunities to study fibrotic diseases. Integrating "-omics" data with humanized mouse models holds great promise for advancing mechanistic studies.
Infectious disease and fibrosis
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Fibrosis, a significant global health challenge with no cure, affects both developed and developing countries. Infections with various viruses can increase the risk of developing chronic diseases and fibrosis, particularly in the lungs and liver. To address this, we leverage humanized organs and mice with a human immune system to uncover the complex mechanisms driving chronic inflammation and fibrosis. By combining in vitro and in vivo approaches, our aim is to deepen our understanding of these diseases and ultimately pave the way for novel therapeutic strategies.
Myeloid cells in cancer
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Neutrophils play crucial, yet poorly understood, roles in cancer. They are a significant component of tumor-infiltrating myeloid cells and can exhibit both pro- and anti-tumor effects. Neutrophils may support tumor growth by promoting tumor cell proliferation or modulating immune responses within the tumor microenvironment or systemically. To explore this, we have developed humanized mice that support the development of human neutrophils, monocytes, and macrophages. This enables us to investigate the roles of various human neutrophil subsets and other tumor-infiltrating myeloid cells in cancer, paving the way for the development of mechanistically validated therapeutics.
Celiac disease
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Celiac disease is an autoimmune disorder that affects 1-2% of the global population. While it has a strong genetic predisposition and a known antigen (gluten), the underlying mechanisms remain poorly understood. Transgenic mouse models have been useful in studying intestinal inflammation in response to gluten, but they do not fully replicate the complexity of the human intestinal immune system and epithelial cell biology. To address this, we are developing humanized mouse models to better understand the mechanisms of immune cell activation and epithelial cell death in the context of celiac disease.