Welcome to the Bhargava Laboratory
Understanding the pathophysiology of Multiple Sclerosis to identify new treatment strategies
Metabolomics in MS
There is a major unmet need for biomarkers of MS disease progression. Our lab is currently focusing on the utility of new “omics” technologies such as metabolomics and lipidomics in identifying both prognostic and diagnostic biomarkers for MS. Metabolomics and lipidomics refer to the use of mass spectrometry coupled with liquid or gas chromatography to identify levels of multiple metabolites / lipid species in biological matrices such as plasma and CSF. Current projects involve utilizing metabolomics to identify a metabolic signature of MS, identifying metabolic pathways that are related to progression in MS and utilizing metabolomics to understand the mechanism of action of the disease modifying agent dimethyl fumarate. We are also tracking a large cohort of patients longitudinally to determine whether serum lipidomic profiles predict progression of disease over time. These studies could help better understand the pathophysiology of the disease and provide markers for use in the testing of new therapies for progressive MS.
Leptomeningeal inflammation in MS
Leptomeningeal inflammation has been noted in relapsing remitting MS as well as progressive MS and has been associated with a more severe disease course and increased cortical demyelination. B cells are an important component of these meningeal infiltrates and in a subset of MS patients, ectopic lymphoid follicle like structures can be identified in the meninges. Meningeal inflammatory infiltrates in MS patients can now be detected on MRI imaging providing a possible marker of therapeutic response for trials targeting this process. However, the testing of potential therapeutic agents is hampered by the lack of a suitable animal model.
We performed ultra-high field MRI (11.7 T) in mice with relapsing-remitting EAE late in their disease course and identified meningeal contrast enhancement that pathologically corresponds to meningeal inflammation. These meningeal infiltrates are composed primarily of B and T cells and are associated with demyelination and axonal damage in the adjacent cortex. These lesions also persist and accumulate over time providing a potential marker to test the efficacy of therapies targeting meningeal inflammation. We are currently in the process of further defining the effects of meningeal inflammation on the adjacent cortex and testing new therapeutic agents that could impact the various components of the meningeal infiltrates.
CNS cell-derived Extracellular vesicles in MS
Extracellular vesicles (EVs) are produced by all cells in the body and play important physiological and pathological roles in intercellular communication. Since EVs express proteins on their surface derived from their cell of origin, multiple groups have developed strategies to isolate EV subsets enriched for a particular cell of origin. For example, L1-CAM is an adhesion molecule primarily expressed on neurons and L1-CAM+ EVs are highly enriched in neuronal proteins suggesting that this sub-set of EVs is enriched for neuronal origin. Similarly, GLAST has been identified as a potential marker to identify astrocyte-derived EVs. We partnered with colleagues at the National Institutes of Aging to apply this method to people with MS to help identify a new platform for biomarker discovery and understanding MS pathophysiology.
We noted in a study of 61 people with MS and 31 healthy individuals that neuronally-enriched EVs (NEVs) from people with MS has markedly reduced levels of synaptic proteins and AEVs from people with MS had elevated levels of multiple complement components compared to healthy individuals. These were interesting findings since pathological studies have demonstrated significant synaptic loss in MS and recent studies have suggested that synaptic loss is mediated by complement deposition on these synapses leading to removal by microglia. Most remarkably, we also showed in this study that there was as striking inverse correlation between levels of NEV synaptic proteins and a number of AEV complement component levels suggesting that higher astrocyte complement production drives synaptic loss in MS.
We are currently funded by the Myelin Repair Foundation to evaluate longitudinal changes in these NEV and AEV markers in people with MS and to link them with imaging markers of neurodegeneration. We are also funded to assess longitudinal changes in a broad range of biomarkers in EV subsets in a large cohort of controls, people with RRMS and PMS. We plan to use these EV subset-based biomarkers to monitor effects of therapeutic interventions - such as the effect of TUDCA on AEV complement in our ongoing trial of TUDCA in PMS.
Additionally, we are in the process of identifying markers of OPC- and oligodendroglia-derived EVs to interrogate ongoing damage or repair within these cell populations, especially in trials of putative remyelinating agents.
The Fruits of Our Labor
Imaging meningeal inflammation in CNS autoimmunity identifies a therapeutic role for BTK inhibition
June 17, 2020
Synaptic and complement markers in extracellular vesicles in multiple sclerosis
Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation
A Collaborative & Diverse Group
Dr. Bhargava is an Associate Professor of Neurology at the Johns Hopkins University School of Medicine. He went to medical school in India at the Christian Medical College (Vellore) and completed his neurology and neuroimmunology training in the US. His goal is to identify new treatments for progressive MS and to help personalize care of people with MS.
Research Post-Doctoral Fellow
Larissa received her MD from the University of Hamburg, Germany in 2021. She has been part of the lab since June 2021. She is leading the work on our extracellular vesicle biomarker project and studying the in vitro effects of metabolites on glial cells. She is an avid hiker and explorer of all the national parks America has to offer.
Research Post-Doctoral Fellow
Saumitra Sen Singh
Saumitra is from India and received his PhD from Banaras Hindu University (BHU), Varanasi, India in 2021. He joined the lab in August 2021 and his project is focused on functional metabolomics studies and investigating molecular mechanism behind the link between alteration in metabolites and multiple sclerosis (MS) in mouse models. In his spare time, he enjoys playing and watching sports with his friends.
Clinical Post-Doctoral Fellow
Dimitrios grew up in Crete, Greece, where he also studied medicine. He graduated in 2020 and joined the lab one year later. He is running two observational clinical trials and he is involved in translational research projects studying the metabolomics and potential biomarkers in MS. Outside of the lab, he enjoys playing basketball at local courts and exploring new places in Baltimore.
Kanak graduated from Johns Hopkins University in May 2020, with a BS in Neuroscience and Writing Seminars. She joined the lab in February 2021 and is the driving force behind our leptomeningeal inflammation in MS. She assists on all active lab projects, including the metabolite studies and clinical trials. In her free time, she enjoys writing poetry and being the lab's Baltimore tour guide.
Deepika graduated from Virginia Commonwealth University with a BS in Health and Science. She is currently a graduate student at Johns Hopkins University studying biotechnology. She joined the lab in August 2022 and is studying EV based biomarkers. Outside of lab, she plays the ukelele and enjoys exploring eateries in the city.
Clinical Research Cooridinator
Sakshi graduated from JHU in May 2022 with majors in Neuroscience and Economics, and has been working with the team since. She is primarily working on a Phase III clinical trial for patients with Primary Progressive MS and is setting up a new Phase III study this year. She is originally from South Jersey and a huge Eagles fan (go birds). In the future, she will be attending medical school.
Latest developments in the Bhargava Lab
Kanak accepted to Graduate school
Kanak will begin her program at University of Toronto in the Fall. Congratulations !! We will miss you.
Research Opportunities at Bhargava Laboratory
October 12, 2020
Research Coordinator/ Research Fellows
We are looking for candidates interested in working in our research group on the clinical side. We are currently beginning two investigator-initiated trials and you would be involved in getting these off the ground and recruiting/ following patients in these trials. Recent grads/ IMG/ FMGs are welcome to apply. Please contact me at email@example.com.
October 15, 2020
We are looking for candidates interested in working in the laboratory on new porojects related to leptomeningeal inflammation in MS or EVs in MS. Prior experience with animal models of disease and in vitro work with neuronal/ glial cells would be a plus. Please contact me at firstname.lastname@example.org.