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Jayasri Das Sarma |
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Molecular and Cellular Virology: Neurological
dysfunction
is a manifestation of several neurodegenerative and autoimmune diseases
of the nervous system, such as Alzheimer's disease, Parkinsons
disease, HIV-1 associated encephalopathy and in Multiple Sclerosis
(MS). Of these, MS is one of the most common demyelinating diseases of
the human central nervous system (CNS) afflicting about 400,000 people
in the United States, primarily in the age group of 20 to 45. The
pathophysiological mechanisms underlying the changes in neurological
function are as yet unresolved, but may include neuroinflammatory
responses to infectious and/or environmental, as well as endogenous
factors. My laboratory is interested in identifying and characterizing
the molecular and cellular pathways involved in the neuroinflammatory
mechanisms of MS, which can provide insights for therapeutic inventions.
Long standing hypotheses on the etiology of MS suggest that an infectious agent
encountered during
adolescence primes a disease process that later appears in the adult
after a variable period of quiescence, when the viral particle may or
may not be present. It is not known what can be the intervening stages
between early age viral infection and later induction of demyelination.
A better insight into the molecular and cellular mechanisms of these
processes leading to MS lies in the systematic study of animal models.
Towards this goal several experimental animal models have been
developed to study the mechanisms of virus-induced demyelination,
including the coronaviral mouse hepatitis virus (MHV) infection.
Infection of mice with neurotropic strains of MHV induces a biphasic
neurological disease with acute meningoencephalitis, followed by
chronic inflammatory demyelination which mimics the pathology of MS. In
MHV induced neuroinflammatory model, demyelination develops when virus
is cleared and encephalitis is resolved. My research interest is
focused on identifying the factors and the pathways used by the MHV to
establish the acute stage encephalitis and the later stage disease
process on two levels. First, what are the genomic controls of the
early stage disease process? Here, using targeted RNA recombination we
are generating recombinant strains of MHV with different encephalitic
and demyelinating properties to study mouse CNS pathophysiology.
Second, for mechanistic studies we use different phenotypic strains to
understand how the variation in the genomic control (viral factors) can
influence the later events of CNS cellular destruction processes.
Understanding the correlation between the early stage of encephalitis
and chronic stage demyelinating disease and the viral factors which may
contribute to the disease progression is helping us to define
pathway(s) underlying the pathological mechanism of MHV induced
neuroinflammation.
The studies are being extended to human viruses
that show
high seropositivity during MS infection. Specific viral genes that
interact with human locus are being targeted for virology and cell
biology studies based on leads from bioinformatic analysis. By building
parallels between mechanism of infection in human and mouse our goal is
to build testable hypothesis that can help us gain better insight into
MS and possibilities of better therapeutic intervention.
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© Copyright 2009, Jayasri Das Sarma, IISER, Kolkata , India |