(mentions CMT) Hope Center explores the common threads among neurological disord

[Guest guest]

Hope Center explores the common threads among neurological disorders

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The wasted muscles and slurred speech of advancing ALS (amyotrophic lateral

sclerosis), the tremors and movement difficulties of Parkinson's disease, the

slow melting of minds beset by Alzheimer's disease - such bundled symptoms are

so striking that most people assume that the neurological afflictions they

signal are unrelated. Not so, says Mark P. Goldberg, MD, director of the Hope

Center for Neurological Disorders.

(Media-Newswire.com) - The wasted muscles and slurred speech of advancing ALS (

amyotrophic lateral sclerosis ), the tremors and movement difficulties of

Parkinson's disease, the slow melting of minds beset by Alzheimer's disease —

such bundled symptoms are so striking that most people assume that the

neurological afflictions they signal are unrelated. Not so, says Mark P.

Goldberg, MD, director of the Hope Center for Neurological Disorders.

" Patients with brain or spinal disease should of course seek treatment from

clinicians specializing in their disorder, but researching specific diseases is

not the fast path to a cure. Research shows that diseases of the brain, spinal

cord and nerves have common threads that can only be discovered on a fundamental

level. When we understand these shared disease pathways, we can begin to find

cures. That is the work of the Hope Center. "

Center without walls

Given the complexity of the central nervous system itself — a dynamic,

multiscaled and sensitive array of profoundly integrated structures and

processes — the Hope Center mandates research in-put from many disciplines. It

includes geneticists, molecular, cell and developmental biologists,

pathologists, engineers, biochemists and clinician-scientists such as

neurosurgeons, pediatricians, internists, psychiatrists, radiologists and

anesthesiologists.

In every sense " a center without walls, " the Hope Center facilitates research by

70 scien-tists on Washington University's medical and Danforth campuses. The

Hope Center's administrative core is in the Biotechnology Building, and its

Program on Protein Folding and Neurodegen-eration will be situated in the new

BJC Institute of Health at Washington University, located at the heart of the

medical campus.

The Hope Center supports innovative research programs through seed grants that

effec-tively leverage traditional grants and contracts as well as private

funding. Basic research and scholarly publication, while thriving, are only the

beginning of the process. The Hope Center's guiding principle is translational

research: supporting the creation of new knowledge about the brain and nervous

system and then enabling its rapid translation into cures, new treatments and

diagnostic tools for clinicians and patients.

" When scientists with different perspectives and training focus on a problem

together, the translational process accelerates, " says Goldberg, who is

professor of neurology, anatomy and neurobiology, and biomedical engineering.

Hopeful response to the times

The Hope Center developed at an intersection of influences. One was Hope

Happens, a foundation the late Wells Hobler established in 2002 to

quickly find a cure for ALS patients like himself. Another was the Center for

the Study of Nervous System Injury, established in 1991 by former Washington

University faculty member Dennis W. Choi, MD, PhD.

At the same time, Goldberg and colleagues like M. Holtzman, MD, the

B. and Gretchen P. Professor and head of the Department of Neurology, had

been impressed with how much progress resulted from collaborative work across

disciplines — an approach that Washington University had encouraged for decades.

They wanted to implement such a sys-tem to solve the staggeringly difficult

questions about brain disease.

" In 2004, Hope Happens approached us about working together, " Goldberg recalls.

" It was good timing for both groups. We had a plan in place, and it was just

what they were looking for. Neurological science was advancing so rapidly that

it was time to begin thinking hard about moving quickly to treatments. "

Organizing the science

To that end, the Hope Center set out to explore neurological diseases' common

mechanisms and effects on brain cells at the level of genes and molecules. Two

basic research themes developed. The first, the Hope Center Program on Protein

Misfolding and Neurodegeneration, is based on the idea that in neurodegenerative

diseases, proteins somehow fold incorrectly after they are formed and then

create problems as they aggregate. The program will be one of five

Interdisci-plinary Research Centers ( IRCs ) formed under BioMed 21, the

university's translational re-search initiative. Led by Holtzman and Alison

Goate, PhD, the and Mae S. Ludwig Professor of Genetics in Psychiatry,

the IRC involves 25 researchers whose teams will occupy five laboratories in the

new BJC Institute for Health building — the hub for BioMed 21 — when the School

of Medicine and -Jewish Hospital open its doors in January 2010.

Among numerous researchers who have made notable discoveries is M.

, MD, PhD, assistant professor of neurology and director of the Hope

Center's Hobler Laboratory. 's innovative therapy for ALS that

targets the mechanism of protein misfolding has advanced to human trials.

The second major research thrust at the Hope Center is the Program in Axon

Injury and Repair. Investigators are seeking to understand how neuronal axons

degenerate — with the new realization that when an axon is damaged, the fiber

itself triggers a new pathway of active degeneration that could be interrupted

with an entirely new kind of treatment. D. Mil-brandt, MD, PhD, the

Clayson Professor of Neurology, found that a particular molecule arrests

the process and then described the pathway; therapies have since been licensed

for clini-cal development. And in April 2009 — in another example among many —

Di, MD, PhD, associate professor of developmental biology,

discovered a complementary second pathway leading to axon degeneration,

suggesting treatments with powerful potential.

" We're getting so close to truly understanding neurodegenerative disorders and

are mak-ing headway with new therapies, " says Holtzman, who credits the Hope

Center's infrastructure for its success in both research and funding. He chairs

a steering committee of senior scientists ( Goate, Goldberg, Milbrandt and

Eugene M. Jr., PhD, professor of neurology and of molecular biology and

pharmacology ) to evaluate progress, with oversight from the Hope Cen-ter's

executive committee. J. Stowe, JD, administrative director, coordinates

the over-all team effort.

Eliminating barriers

Still another way the Hope Center ensures progress is by knocking down

conventional barriers, creating smoother, faster pathways to translation. In

addition to putting the right minds together to solve complicated problems —

such as matching basic scientists with clinicians — adminis-trators have

provided core facilities for animal models, amyloid-beta microdialysis,

neuroimaging and transgenic and viral vectors. New facilities, equipment and

instrumentation — most recently, the medical school's first atomic force

microscope — are added, funding permitting, in response to investigators' needs.

And a new collaboration with the Office of Technology Management recently has

been implemented to help scientists disclose and patent inventions and to ready

their ideas for biotechnology or drug company licensing.

" In one sense, it's good that our researchers are distributed across the

campuses, " says Goldberg. " They can work near their home departments without

changing affiliations and neighbors. The only downside is that while we gather

regularly, we don't interact every day. Bumping into people in a hallway can be

at the heart of science. Finding new ways to bring scientists together — now,

there is a challenge! "

H. Baloh, MD, PhD, deciphers the molecular mechanics of neurodegenerative

disease. Two of his research focuses are amyotrophic lateral sclerosis ( ALS ),

also known as Lou Gehrig's disease, and Charcot-Marie-Tooth disease ( CMT ). As

neurons die in the motor pathways of an ALS patient's brain and spinal cord,

muscles atrophy. The patient becomes profoundly weak, unable to speak or

swallow, and eventually dies from respiratory failure three to five years after

di-agnosis. In contrast, though CMT involves degeneration of similar motor

pathways, it progresses slowly over a patient's lifetime, typically causing foot

drop, foot deformities, falls and hand weakness as peripheral nerves

deteriorate.

Baloh's lab is investigating a gene known as TDP-43, a key regulator of

messenger RNA splicing, which edits protein-building instructions from DNA to

allow proper protein assembly. Abnormalities can radically alter cellular

function.

During collaborative research published in ls of Neurology in February 2008,

Baloh and Hope Center colleagues, including Nigel J. Cairns, PhD, research

associate professor of neurology and of pathology and immunology, and Alison

Goate, PhD, professor of neurology and of genetics, linked a mutation in TDP-43

to an inherited form of ALS and are now creating a mouse model for the disease.

They will then compare animal models, cultured neurons and cell lines to

existing models of ALS based on mutations in the SOD1 gene.

" Our expectation, " Baloh says, " is that understanding how disease mutations in

TDP-43 and SOD1 cause neurodegeneration will allow us to identify effective

treatments. "