Gonçalo Castelo-Branco

Spatial omics is a cutting edge field that enables unprecedented high-resolution mapping of molecular features, such as RNA, proteins, and metabolites, directly within intact tissues. These technologies are transforming how we study biology and disease by revealing the spatial organization of cell states and tissue architecture. Sweden has played a leading role in the development of spatial omics, including key technologies such as spatial transcriptomics, in situ sequencing, multiplexed imaging, among others. Building on this foundation, we propose a planning grant to prepare a national Cluster of Excellence in Spatial Omics that bridges fundamental technology development with biomedical and clinical applications.The planning initiative brings together researchers from KI, KTH, and Stockholm University, representing expertise in molecular biology, engineering, data science, life sciences and translational medicine. During the six-month planning period, we will organize workshops and coordination meetings between these researchers and the wider life sciences community to brainstorm and identify scientific priorities and milestones, define collaborative structures, including a research school, and ensure alignment with clinical, infrastructural, and societal needs. The outcome will be a roadmap for a full cluster proposal and a long-term strategy to foster Swedish leadership in this transformative field.

Multiple sclerosis (MS) is a neurological disease characterized by autoimmune attack in the central nervous system, targeting oligodendroglia (OLG), and their myelin, which ensheaths neuronal axons. Environment factors and genetic susceptibility play important roles in the etiology of MS. Immune genes harbors MS risk single nucleotide polymorphisms (SNPs)/variants. Thus, genetic predisposition affecting the adaptive immune system is currently thought to be involved in MS. Despite the extraordinary progress in immune-based therapies for MS, these have limited efficacy in the progression of MS. While OLG are mostly considered as mere passive targets in MS, our research indicates that OLG might have an active role in MS and that risk SNPs/variants might contribute to MS by affecting OLG biology. My research group aims to investigate  the role of OLG in disease etiology and progression in MS. We aim to perform detailed single-cell and spatial mapping of the transcriptomic and epigenomic landscapes of OLG in MS. We will assess functional roles of OLG in MS etiology and progression, by developing humanized models to study OLG biology in neuroinflammation, and by performing functional analysis of candidate MS-risk SNPs in OLG. Combining single-cell/spatial omics, genome-editing and functional assays in humanized mice models of MS will lead to unique insights on the role of OLG and SNPs in MS etiology and progression, and advances in the discovery of novel targets for MS therapies.

Multiple sclerosis (MS) is a neurological disease characterized by autoimmune attack targeting oligodendroglia (OLG) in the central nervous system (CNS), and in particular their myelin, which ensheaths neuronal axons. Genome-wide association studies (GWAS) have led to the identification of hundreds of single-nucleotide polymorphisms (SNPs) and variants that are associated with MS risk. Many of these are located near genes associated with immune cells, indicating a key role for these cells in MS. Using single-cell omics approaches, we recently found that OLG present chromatin accessibility or express genes associated with some of these SNPs/variants, both in health and disease. Here, we hypothesize that OLG have a more active role in MS than previously anticipated, and therefore we will determine the function of MS SNPs/variants in OLG in the context of MS, using humanized mouse models, patient samples and new single-cell omics techniques recently developed in my group. We will 1) characterize in-depth the transcriptomic and epigenomic landscape of human and mouse OLG in the context of MS, to identify putative genes affected by the SNPs/variants

2) perform CRISPR-guided editing of a cohort of the identified SNPs/variants in human OLG, and determine the consequences of the editing at a) an epigenomic and transcriptional level, linking specific SNPs/variants to their bona-fide target genes, and b) a functional level, by performing an array of functional assays targeting myelination, cell survival, and immune function, both in vitro and in humanized mouse chimeras in which engineered human OLG have been transplanted. We will use single-cell and spatial omics technologies, such as nanoCUT&Tag and spatial CUT&Tag, among others which we have recently developed in my research group. The results of this project will yield unique insights into the role of OLG and the identified SNPs/variants in MS, and thereby pave the way to novel therapeutic avenues for this disease.