Project Details
Projekt
“Mitochondrial” Regulation of Pemphigoid Diseases
Applicants
Dr. Misa Hirose; Professor Dr. Saleh M. Ibrahim
Subject Area
Dermatology
Term
from 2015 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 269234613
Current concepts of the pathogenesis of autoimmune diseases postulate that, in general, the pathogenesis of these diseases is critically determined by both genetic and environmental factors. Research into the genetics of pemphigoid diseases (PDs) is still in its infancy, and, consequently, the genetic variants promoting the development of PDs are still largely elusive.In the 1st FP of the CRU 303, we therefore initiated the first genome-wide association study (GWAS) in BP patients to identify candidate genes. By now, we have already profiled the genome of 447 BP patients and 436 age-matched controls. This has revealed a strong, genome-wide significant (p < 0.5 x 10-8) association of SNPs at the HLA locus (6p21.1-21.3). In addition, multiple variants outside the HLA locus, such as ZNF385D and FGF14, were also identified.The GWAS data were merged with results of a preliminary gene expression profiling of the skin and whole exome sequencing to pinpoint major pathways involved in the pathogenesis of BP. In addition, we have sequenced the mitochondrial (mt)DNA of 95 BP patients. Collectively, these analyses suggested, in addition to classical genes of the immune response, a significant contribution of multiple mitochondria-associated metabolic pathways and of pathways implicated in epithelial cell adhesion, such as the EXPH5 pathway, to the pathogenesis of BP. We have subsequently started to address the functional relevance of mitochondria-associated pathways in BP using conplastic mouse strains, a rare resource, we had previously developed, which allows dissecting the contribution of mtDNA mutations to disease. Our preliminary findings, among others, suggest that mitochondrial gene variants may modulate PD skin inflammation by altering the tissue levels of short chain fatty acids. Furthermore, we have found that the gut microbiota in mice is co-determinant to a significant part by mitochondrial genes. In the 2nd FP, we will therefore focus more on the functional role of mitochondria-associated pathways in the pathogenesis of PDs. We will use both out conplastic mouse strains as well as BP patient-derived cells to determine the impact of individual variants in mitochondrial genes on PD skin inflammation. In addition, we will also sequence the mtDNA of additional BP patients to enhance the resolution of our genetic study. Finally, we will elucidate, in collaboration with P2 and the Z2-Project, the crosstalk between nuclear DNA and mtDNA and its impact on the skin microbiota and PD.
DFG Programme
Clinical Research Units
