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UTHSCSA
they have no symptoms. The disease is thought to be triggered
in a genetically susceptible individual by a combination of one or
more environmental factors. While there is no current cure for
MS, treatments can help speed recovery from attacks, modify the
course of the disease and allow better management of symptoms.
Treatments for MS target the immune system and are generally
called immunomodulators.
A basic nerve cell consists of dendrites on the receiving end, a
cell body (soma) and a long, thin axon that runs to the terminal
end. The axon has an insulating sheath made up of specialized
glial cells known as myelin that covers its entire length leaving in- research has the potential to provide clues for axon recovery in
termittent gaps that are devoid of myelin. The thick multilayered
myelin sheath facilitates fast conduction of nerve impulses in
axons and is therefore critical for fast signal transmission and
proper function of axons in the nervous system. The gaps pro-
mote this conduction (saltatory conduction). As Dr. Bhat’s team
moved from the fruit fly model to targeting the genes in mouse
models, they focused on uncovering the specific molecular mech-
anisms of the nerve dysfunction and came to realize that it was
caused by a breakdown of the axon’s myelin sheath.
MOUSE MODELS
Dr. Bhat’s research has focused on close to 10 genes, and
demonstrated the resultant neurological dysfunction after their
manipulation. Their work continues to focus on the genetic and
molecular basis of the highly complex and intricate interactions
between the neurons and glial cells in the nervous system. Glial
cells not only play a key role in axonal insulation for proper and
fast transmission of nerve impulses, but also in blood-brain barrier
formation and axonal guidance.
Part of Dr. Bhat’s research in mouse models is to determine
how long the axon remains functional in the process of myelin
breakdown. Many questions emerge, such as: At what point does
the damage significantly compromise motor function? At what
point(s) can the process be halted or reversed? At what point is
the loss of function simply beyond recovery? Where is the thresh-
old for “rescuing” a paralyzed mouse? What is the treatment
process for rescuing a paralyzed mouse? Can one get it to the
point of being able to ambulate again?
Addressing these questions requires a genetic strategy, which is
also a significant part of Dr. Bhat’s work now. Regrettably, it takes
years of meticulous experiments. Determining a terminal break-
down threshold of the axon — and a successful therapeutic in-
tervention before that threshold is reached – is an important goal
not only for MS, but has implications in many other neurological
disorders, from Parkinson’s disease to ALS and spinal cord injury.
It has taken Dr. Bhat’s team a decade to systematically knock
out the genes of interest to prove that each was necessary and suf-
DEAN’S MESSAGE
ficient to impair nerve function. One of the challenges posed by
the knock out mice was that they had a short lifespan, so Dr.
Bhat’s team had to find a way to take a healthy adult mouse with
a certain genetic makeup, and knock out the gene in these adults.
They devised a strategy to suppress the gene(s) after the mice were
mature. The mice would then take approximately three months
for the symptoms to materialize.
Currently, one of the goals is to “turn the genes back on” and
see if the nerves are able to recover their function. Will these
nerves function after 30, 60 or even 90 days of no function? This
patients with MS, and hopefully will lead to therapeutic remedies.
Dr. Bhat’s team is looking into all aspects of the equation: the
pathology and the time course of deterioration, how the post-
synaptic tissue processes work, and how to halt and/or reverse the
lack of function on the receiving end.
INSPIRED HIS DAUGHTER
Dr. Bhat always gives all credit to his mentors, trainees and col-
laborators, which include a dedicated team here, and researchers
at NYU Medical Center, UNC at Chapel Hill, University of
Chicago and Virginia Commonwealth University, as well as to
his continued federal and private funding. He is supported by
grants from the National Institutes of Health, the National Mul-
tiple Sclerosis Society, the Zachry Foundation for Neuroscience
Research, the Simons Foundation as well as generous funds from
the School of Medicine at the Health Science Center.
All of the work his team and collaborators have performed is
cataloged in a number of seminal publications in various high-
profile journals, including Nature, Neuron, Cell and The Journal
of Neuroscience, as well as in many others. Some of his work has
appeared on the covers of these journals, which adorn his office.
On a personal level, Dr. Bhat has successfully inspired his
daughter, Heba, who is now a neuroscience major at UT Austin,
who no doubt has inherited the genes to also be a terrific scientist.
We are fortunate to have him among our faculty, and his work
has a tremendous potential to help many people with neurological
disabilities around the world. To read more about his research, or
contact him, please visit our website at
http://physiology.uthscsa.edu .
Francisco González-Scarano, MD, is dean of
the School of Medicine, vice president for medical
affairs, professor of neurology, and the John P.
Howe III, MD, Distinguished Chair in Health
Policy at the University of Texas Health Science
Center at San Antonio. His email address is
scarano@uthscsa.edu.
visit us at www.bcms.org 33