Oda, Hirotsugu - CAP 39

Genetics-driven Precision Immunology for Unraveling Chronic Inflammatory Disease Mechanisms

Dr. Hirotsugu Oda

CECAD Research Center

CMMC - PI - CAP 39

hirotsugu.oda@uk-koeln.de

0221 478-84088

Lab Website

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

CECAD Research Center

Joseph-Stelzmann-Str. 26

50931 Köln

Introduction

Chronic inflammation plays a central role in various human diseases, including rheumatic conditions. Current research strategies largely rely on hypothesis-driven animal studies, highlighting the need for human-centric, forward-genetic approaches. We propose a novel concept of human molecular immunology, leveraging genome sequencing to identify new genetic drivers and elucidate causal molecular mechanisms of chronic inflammation in humans. Furthermore, tissue-regulated inflammation is studied using genetic models, integrating insights from both established and newly discovered inflammatory conditions. By advancing genetics-guided precision medicine, this research aims to pave the way for targeted therapies in chronic inflammatory diseases. (Figure 1)

Figure 1

Fig. 1: Concept: Genetics-driven Precision Immunology for the novel mechanistic understanding of inflammation.

Clinical Relevance

Identifying Mendelian causes of inflammation provides fundamental genetic insights that drive clinical applications for chronic inflammatory diseases. Novel disease mechanisms and life-saving targeted interventions have been uncovered, including SHARPIN deficiency (Oda et al., Nat Immunol, 2024) and cleavage-resistant RIPK1-induced autoinflammation („CRIA“; Lalaoui*, Boyden*, Oda* et al., Nature, 2020). These findings highlight the potential of genetics-guided precision medicine in diagnosis and treatment.

Figure 2

Fig. 2: SHARPIN deficiency underscores the role of clinically targetable TNF-induced cell death in humans.

Aims & Approaches

We aim to address two central hypotheses:

A subset of rheumatologic conditions currently considered multifactorial may have monogenic origins
Mendelian forward-genetic screening in patients will reveal novel molecular mechanisms that cannot be identified solely through hypothesis-driven animal studies

As a proof of concept, we identified novel Mendelian mutations in Cogan’s syndrome (CS), an ocular-audiovestibular disorder, revealing key molecular mechanisms linked to immunometabolism. Furthermore, we identified multiple novel mutations on cell death pathways, providing causal evidence connecting excessive cell death and inflammation. Building on these findings, we integrate genome sequencing, cellular assays and animal-models to elucidate clinically targetable novel molecular pathways in human immunity.