Using single-cell technology and network analyses to unravel the complexity of inflammation related to Multiple Sclerosis (MS).
Our working hypothesis for this line of research is that distinct patterns of central nervous system (CNS) inflammation occur in MS patients which can be used to differentiate different clinical courses, such as converting and non-converting clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and primary progressive MS (PPMS). To test this hypothesis, we are integrating cutting-edge technologies (scRNAseq, ATAC-seq, DNA methylation profiling, and multiplexed immunosorbent assays) with innovative network analytical approaches, which will enable the detailed study of CNS inflammation and CNS damage, both at the cellular and molecular system levels. The long-term goal of this research is to provide disease-specific targets and pathways for the prevention and treatment of MS, which will be especially significant for the long-term management of the disease.
Characterization and clinical correlate of meningeal inflammation in a model for neurodegenerative diseases.
Our working hypothesis for this research is that meningeal inflammation is temporally dynamic, and its inflammatory profile transforms as a function of the severity of CNS damage and neurological impairment. To test our hypothesis, we utilize Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) model of progressive neurodegeneration and high throughput technologies such as scRNAseq, flow cytometry, and multiplex Luminex profiling. These studies will provide an essential platform for investigating the role of meningeal inflammation in common neurologic conditions, including MS. This will ultimately favor the development of improved treatments and disease monitoring plans, as my findings will lead to the development of new treatment targets and fluid biomarkers for degenerative diseases.
Sexual dimorphism in neurological conditions: improving our understanding of neuroinflammation.
The overarching goal of this research is to determine how sex differences in CNS immune responses affect disease progression in MS. To determine this, we are utilizing both human-based research and prototypic neurodegenerative murine models. Both proposed approaches are ideal for examining sex dimorphism in MS and related CNS immune functions. The successful completion of this research will make significant contributions to understanding: 1) the development and maintenance of CNS inflammation in MS, 2) how CNS inflammation affects disease progression, 3) what sex biasing factors, e.g., hormones and sex chromosome, mostly affect a sexually dimorphic disease progression, and 3) how disease progression can be predicted and/or prevented in a clinical setting.
MRI measures of neurodegeneration in two clinically distinct murine models of multiple sclerosis.
Recent advances in neuroimaging offer promising opportunities to develop and validate biomarkers of neurodegeneration as valuable adjuncts to available diagnostic and monitoring tools. To this end, recent work performed at Vanderbilt University Medical Center (VUMC) led to the technical development of two advanced quantitative MRI techniques, namely selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and diffusion imaging using the spherical mean technique (SMT). SIRqMT delivers the pool saturation ratio (PSR), a metric with increased specificity to myelin integrity; MST delivers the apparent axonal volume fraction (Vax), which provides an indirect estimate of viable axons. Due to their physic properties, SIR-qMT and SMT provide a novel framework for the non-invasive quantification of myelin and axonal injury, respectively. The goal of this research is the in vivo and longitudinal application of SIR-qMT and SMT in two clinically distinct murine models of MS, TMEV-DD, and relapsing experimental allergic encephalomyelitis (R-EAE), which provide a unique opportunity to validate the novel myelin and axonal specific techniques against a background featured by variable degrees of inflammation and neurodegeneration.
Targeting the complement system in mouse models of neurodegeneration utilizing highly CNS penetrant therapeutic strategies
An emerging drug target for neurodegenerative disorders is the complement system, especially the complement protein C1q. The complement system, also known as the complement cascade, is a critical component of the immune system. It usually functions by promoting the removal of pathogens and damaged tissue products from the body. The complement protein C1q is the first subcomponent of the classical complement cascade, and its abnormal accumulation likely plays a role in triggering prolonged inflammation and cellular death. In line with this statement, high amounts of C1q have been described in the brain of patients affected by neurodegenerative disorders, including MS, being implicated in promoting brain damage. TMEV-IDD is a mouse model of prolonged brain inflammation and neuronal death. We have recently shown that C1q is highly present in the brain of mice with TMEV-IDD and that increased amounts of C1q relate to a worse clinical disability. With this research, we aim to evaluate the therapeutic blockade of C1q by using a specialized anti-C1q antibody and highly CNS penetrant therapeutic strategies in TMEV-IDD. Overall, our studies focus on behavioral tests of everyday skills and neuropathological features. If successful, this work would provide evidence for the involvement of C1q in the mechanisms driving neurodegenerative diseases, thereby supporting the use of C1q blockers in improving neurologic impairment in neurodegenerative diseases like MS.