Project description:Metabolomic Analysis in Secondary Progressive and Benign MS. Preliminary data: We have conducted whole blood cell microarray comparing gene expression profile of 20 SPMS and 13 BMS patients. The data revealed significant increase in pathways involving iron ion binding, oxygen transporter activity and hemoglobin functions. Specifically, the identified down regulated genes are involved in interacting selectively and non-covalently with iron (Fe) ions. Heme has been described as a potent pro-inflammatory molecule that can induce multiple innate immune responses, and cause excessive iron and heme-induced oxidative stress and cell death. In the brain, it causes neurodegeneration. In addition, our microarray preliminary results also show a statistically significant increase in arachidonate 12-lipoxygenase activity in SPMS compared to benign MS. Specific aim. To validate metabolites and lipid biomarkers in serum samples from patients with benign and secondary progressive MS. Our central hypothesis is that the gene expression in various types of multiple sclerosis likely create a systematic metabolomic/lipidomic environment that leads to progression in MS. We plan to compare and contrast metabolomics in SP-MS to BMS patients using the innovative technology at the Metabolomics Research Core at the University of Michigan. By monitoring lipid and metabolite changes in SP and BMS patients, we aim to identify molecular processes and biomarkers of axonal damage for MS. Then, we plan to translate such metabolomic biomarkers to correlate with our rich clinical, immunological and imaging readouts. The goal of this project is to develop a blood-based test to differentiate SP-MS from BMS patients. To accomplish this, we will first identify the gene expression signature associated with of SP-MS. Then, we will correlate these gene expression changes with lipids and metabolite changes in the blood by metabolomic network analysis. Because metabolism is the final fingerprint of functionality and has been implicated in neurodegeneration, metabolomic network analysis can be used for refining the relationships between specific gene expression and metabolites and axonal damage in progressive MS. Ultimately, we hope to develop blood, CSF and stool-based assays, and use this comprehensive profile to predict susceptibility and progression of MS. This is a new and innovative idea, which will hope to lead to future diagnostic and therapeutic development in MS.

Project description:Background: Multiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, although it is known to be associated with the HLA region on 6p21.32. Recently, a picture of chronic cerebrospinal venous insufficiency (CCSVI), consequent to stenosing venous malformation of the main extra-cranial outflow routes (VM), has been described in patients affected with MS, introducing an additional phenotype with possible pathogenic significance. Methods: In order to explore the presence of copy number variations (CNVs) within the HLA locus, a custom CGH array was designed to cover 7 Mb of the HLA locus region (6,899,999bp; chr6:29,900,001-36,800,000). Genomic DNA of the 15 patients with CCSVI/VM and MS was hybridised in duplicate. Results: In total, 322 CNVs, of which 225 were extragenic and 97 intragenic, were identified in 15 patients. 234 known polymorphic CNVs were detected, the majority of these being situated in non-coding or extragenic regions. The overall number of CNVs (both extra- and intragenic) showed a robust and significant correlation with the number of stenosing VMs (Spearman: r=0.6590, p=0.0104; linear regression analysis r=0.6577, p=0.0106). The region we analysed contains 211 known genes. By using pathway analysis focused on angiogenesis and venous development, MS, and immunity, we tentatively highlight several genes as possible susceptibility factor candidates involved in this peculiar phenotype. Conclusions: The CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease.

Project description:Background: Multiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, although it is known to be associated with the HLA region on 6p21.32. Recently, a picture of chronic cerebrospinal venous insufficiency (CCSVI), consequent to stenosing venous malformation of the main extra-cranial outflow routes (VM), has been described in patients affected with MS, introducing an additional phenotype with possible pathogenic significance. Methods: In order to explore the presence of copy number variations (CNVs) within the HLA locus, a custom CGH array was designed to cover 7 Mb of the HLA locus region (6,899,999bp; chr6:29,900,001-36,800,000). Genomic DNA of the 15 patients with CCSVI/VM and MS was hybridised in duplicate. Results: In total, 322 CNVs, of which 225 were extragenic and 97 intragenic, were identified in 15 patients. 234 known polymorphic CNVs were detected, the majority of these being situated in non-coding or extragenic regions. The overall number of CNVs (both extra- and intragenic) showed a robust and significant correlation with the number of stenosing VMs (Spearman: r=0.6590, p=0.0104; linear regression analysis r=0.6577, p=0.0106). The region we analysed contains 211 known genes. By using pathway analysis focused on angiogenesis and venous development, MS, and immunity, we tentatively highlight several genes as possible susceptibility factor candidates involved in this peculiar phenotype. Conclusions: The CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease. 8 female and 7 male MS patients

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Biomarkers for different types of Multiple Scelerosis (MS) (BMS vs SPMS lipidomics)

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