The main focus in Neurogenomiks is on the basic investigation of two neurological diseases that share inflammatory components, i.e. multiple sclerosis (MS) and cerebrovascular disease.
MS is an autoimmune disease affecting the central nervous system, predominantly affecting young women. Over recent years, single nucleotide polymorphisms (SNPs) in well over 100 gene loci have been robustly associated with the disease. However, the functional mechanisms by which most of these SNPs cause MS are still largely unknown. We are working on a series of MS risk genes including ANKRD55, IL22RA2, IL12A and IL12B. ANKRD55 is a gene with unknown function which we were the first to report as risk gene for MS. ANKRD55 is also shared as risk factor with four other autoimmune diseases. The gene is expressed in peripheral immune and neuronal cells as well as microglia and produces 2 protein-coding transcripts and one long noncoding RNA. We will decipher the biological function of the protein isoforms via interactome analysis, determine the mechanism of their nuclear import, identify immune subsets expressing the 3 isoforms, determine the function of the lncRNA isoform, and assess the role of ANKRD55 in neuroinflammation in an ANKRD55 knockout mouse model for Experimental Autoimmune Encephalomyelitis, a demyelinating disorder recapitulating the key pathological hallmarks of MS. Following a fine-mapping of the IL22RA2 gene, which codes for a soluble high-affinity antagonist of the cytokine IL-22, we identified a non-synonymous rare SNP strongly associated with risk for MS, that appears to affect the secretion efficiency of the protein. To further our investigation, we will perform a thorough analysis of the secretory pathway of IL22RA2 involving proteomic as well as functional approaches, and study in more detail its natural producer cells, i,.e. dendritic cells (DCs), a crucial category of antigen-presenting cells. We will also study the IL12A and IL12B genes, that also emerged as MS risk genes expressed in DCs, and that produce the p35 and p40 subunit constituents of the therapeutically very important heterodimer cytokines IL-12, IL-23 and IL-35. To enhance our insights in the role of DCs in MS, we will determine the MS risk transcriptome, and its regulation in tolerogenic and immunogenic DCs. We are also studying the processes regulating heterodimer assembly of IL-12 family subunits (p35, p40, p19, p28, EBI3) in the endoplasmic reticulum prior to their secretion and have identified a series of factors interacting with selective subunits through mass spec analysis of their interactomes. We will advance this work through functional studies including assessments in knockout models.
Cerebrovascular disease is the first cause of death in women and the third in men. The instability of carotid atheroma plaque is a risk factor for the development of cerebrovascular event. Although a proportion of patients do not show any type of symptoms while presenting atheroma plaque in their carotid arteries ("asymptomatic patients"), the destabilization and rupture of carotid plaques can cause an ischemic episode with nefast consequences ("symptomatic patients"). However, the process by which the plaque becomes instable is not a random process and evidence exists pointing to biological mechanism. In the context of this research line we will perform a transcriptomic analysis in isolated smooth muscle cells (SMCs) from a well characterized cohort of "symptomatic" and "asymptomatic" atheroma plaques to identify differences in gene expression, new transcripts, SNPs, etc. Also our aim is to fully characterize the subtypes of smooth muscle cells (SMCs) isolated from symptomatic and asymptomatic plaques. Finally, we will evaluate full carotid atheroma plaques from both groups to identified morphological differences, to quantify cell types abundance and analyze the potential association with symptomatology.
Life & Medical Sciences
- Biosciences & Health
- Functional analysis of the multiple sclerosis risk genes IL22RA2, IL12A, IL12B and ANKRD55
- Analysis of the multiple sclerosis risk transcriptome in dendritic cells
- Mechanism of heterodimer assembly of IL-12 type cytokines (IL-12, IL-23, IL-27 and IL-35)
- Transcriptome of carotid atherosclerosis
- Characterization of smooth muscle cells in carotid symptomatology