Our goal is to discover novel human genetic immune disorders with chronic inflammation and fibrosis, aiming to pave a direct way toward molecular targeted therapies for age-associated chronic diseases.
Inflammation and fibrosis are essential physiological responses against disruption of homeostasis such as infection and tissue injury. In age-related contexts, however, these processes also initiate and amplify pathological aging cascades, known as “inflammaging” and “fibroaging”. Importantly, most of the current investigations in the field are still largely dependent on animal models, which critically restricts our understanding of the aberrant organismal consequence of aging in humans. Encouraged by our successful experiences in precision immunology, we aim to discover novel human genetic immune disorders through sequencing approaches, by learning novel molecular hypotheses directly from patients with chronic inflammation and fibrosis.
We learn directly from patients with severe genetic immune dysregulation, not only to expand our knowledge of the human immune system, but also to propose novel genetics-guided molecular targeted therapies.
Our main research goal is to investigate the mechanisms and the organismal consequences of chronic inflammation and fibrosis in humans. First, we aim to elucidate the genetic architecture of the patients with genetic inflammation and fibrosis through local and international genomic consortia. We combine both forward- and reverse-genetic approaches to bring new insights to the patients. Another focus of the group is to understand the immunological mechanisms underlying these genetic conditions, aiming to propose novel molecular therapies. We are particularly interested in the intercellular crosstalk underlying recently discovered inborn errors of immunity and fibrosis with genetic alterations in RIPK1 and STAT4. A further topic of our group is to investigate the activation and the regulation of the inflammasome, a supramolecular protein complex inducing the inflammatory cell death ‘pyroptosis’.
Our team has been successful in establishing evidence for genetics-guided precision immunology. We discovered a novel genetic inflammatory disease named ‘CRIA’. CRIA is caused by genetic alterations in RIPK1 conferring resistance to caspase-mediated proteolytic cleavage. We further investigated the mechanism of how the uncleavable RIPK1 augments cell death-induced inflammation downstream of TNF pathways (Nature 2020). We have next described ‘sharpenia’, caused by a deficiency in SHARPIN, a critical scaffold of the linear ubiquitylating protein complex LUBAC. We have revealed the critical contribution of cell death by TNF superfamily members, which enabled a life-changing treatment of sharpenia by TNF inhibitors (in revision). Finally, we have reported STAT4 gain-of-function in life-threatening genetic inflammatory fibrosis, where our genetic diagnosis has proved JAK inhibitors as an effective targeted therapy (NEJM 2023).