Research:  Source of Hope

Building a Premiere Neuroscience Group

Diseases that affect the brain are some of the most destructive and debilitating.  Most of us have seen the effects that illnesses such Alzheimer’s disease, Parkinson’s disease and ALS

(Lou Gehrig’s disease) have had on friends and loved ones.  It’s heartbreaking to witness the diminishing capacity, or the loss of life itself, that these diseases exact.

Improved treatments are emerging and great strides have been made in recent years, but truly effective means of preventing, eliminating or successfully treating them remain elusive.  Hope resides in research laboratories where dedicated biomedical scientists are searching to more deeply understand the incredibly complex workings of the brain and central nervous system.

At the University of North Dakota (UND) School of Medicine and Health Sciences, researchers are working diligently to uncover the underlying causes of these neurodegenerative diseases.  We

have developed a “center of excellence” where a cluster of researchers concentrate, with laser-sharp focus, on investigations aimed at finding the answers to why and how healthy brain function is disrupted.

Their efforts were rewarded in 2002 when the UND medical school received $10.3 million in funding for five years for our Center of Biomedical Research Excellence (COBRE).  We recently received a renewal of this grant, for $10.1 million over five years, from the National Institutes of Health (NIH), based in Bethesda, MD.

Along with their research colleagues, Jonathan Geiger, Ph.D. (left), COBRE principal investigator, and Brij Singh, Ph.D., collaborate on investigations designed to broaden scientists’ understanding of how the brain functions.

The project is titled “Center of Biomedical Research Excellence (COBRE) on the Pathophysiological Signaling in Neurodegenerative

Diseases,” says principal investigator Jonathan Geiger, Ph.D., chair and professor of pharmacology, physiology and therapeutics.  It’s the latest step in the school’s “focused

commitment to establish a premiere neuroscience group here at UND and builds on progress made in the past five years through NIH funding for our COBRE-supported neuroscience research program.”

“We have achieved a lot in the past five years and have built quite a strong group of researchers in the area of neurodegenerative

diseases,” Geiger said.   “But we

can’t stop here.  We’re at a point where we need to continue to grow and strive for excellence in everything we do.”

The goal of this project “is to enhance and expand our ability to better understand causes of and identify treatments for such devastating neurological disorders as Alzheimer’s and Parkinson’s diseases and epilepsy by focusing the efforts of our researchers on the mechanisms within the brain that lead to these diseases,” he said.

This is a very exciting opportunity for our researchers who dedicate their professional lives to advancing the scientific knowledge necessary to develop better treatments for these

devastating diseases which cause so much human misery.  Just as worthwhile, in this creative environment of inquiry and discovery, students are inspired by faculty members to continue the

quest to reach higher levels of achievement in the biomedical sciences.

“COBRE represents an extraordinary effort by our investigators to build a nucleus of outstanding scientists whose research is focused on discovering new, critically important knowledge about diseases of the brain,” said UND President Charles Kupchella.  “We are especially pleased that their success brings us closer to achieving

our goal of becoming one of the top 100 doctoral/research universities in the nation, as outlined in our strategic plan.”

“We are extremely proud of the leadership and extraordinary effort by Dr. Geiger that has resulted in the renewal of the COBRE grant,” said H. David Wilson, M.D., dean of the UND medical

school.  “It is most unusual for renewal to be awarded on the first attempt, and we congratulate him on this remarkable accomplishment.

“Under his guidance, our researchers will continue to advance knowledge and understanding of diseases in the brain that greatly diminish quality of life,” he added.  “In the highly competitive research arena, the excellence of their work has been recognized and rewarded by the NIH, which affirms that our studies hold promise for improving treatment for millions who suffer from neurodegenerative diseases.”

The purpose of the COBRE grant is to increase the competitiveness of UND’s biomedical researchers for extramural grants through extensive mentorship and funding of five research

projects and smaller pilot grants, Geiger said.  By supporting and guiding these researchers, it is hoped that their work will advance to a level of quality that will attract future substantial funding from federal and other agencies.

Projects to be carried out through the COBRE grant are aimed at uncovering new information that will lead to better treatments for:

          --epilepsy

          --Parkinson’s disease

--Alzheimer’s disease

--neuroinflammation (a condition that is involved in virtually all neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, HIV-related dementia and

multiple sclerosis)

--traumatic brain injury (analyzing potential to regenerate nerve tissue to restore function)

In addition to Geiger, researchers involved in this COBRE grant are:  Saobo Lei, Ph.D., Othman Ghribi, Ph.D., and Thad Rosenberger, Ph.D., assistant professors of pharmacology, physiology and therapeutics; Brij Singh, Ph.D., assistant

professor of biochemistry and molecular biology, and John Watt, Ph.D., assistant professor of anatomy and cell biology.

Geiger also expects to hire at least two neuroscience faculty members with expertise in molecular/genetics and/or proteomics, which are promising and powerful new approaches to scientific investigation.

Biomedical researchers at the UND medical school also are very active in educating and training the next generation of scientists, physicians and physician-scientists, he emphasized, and many

have received awards and recognition for their teaching excellence.

“In the big picture, the school’s research enterprise is very important to the vitality of UND’s academic mission,” he said.   “It is also a powerful economic driver for the state of North Dakota.”

Diet and Alzheimer’s - is there a link?

Othman Ghribi, Ph.D., analyzes the role that diet plays in   Alzheimer's disease.

Othman Ghribi, Ph.D., studies Alzheimer’s disease on two fronts: one related to the role that cholesterol may play in the development of the disease and another concerning how caffeine may affect the progression of the disease.

Unfortunately, people who suffer from Alzheimer’s have limited options for treatment because the disease is extremely complex and what causes it is not clear, says Ghribi who has been

studying the disease for more than 10 years.

Although genetic factors are thought to play a role in a small minority of cases, perhaps up to five percent, the overwhelming majority is thought to be caused by environmental influences

including exposure to environmental toxins; diet; having diabetes, and other factors that predispose one to develop the disease.

Ghribi is most interested in the risk factors that may induce Alzheimer’s disease, or make it worse.  His long-term objective is to identify risk factors and mechanisms by which these factors trigger the disease.  He is especially interested in cholesterol as it relates to Alzheimer’s disease, he says, particularly “how

high cholesterol levels in the blood can lead to

the hallmarks of Alzheimer’s disease (AD) that we see in patients.”

“Epidemiological studies have shown that people who, at middle age, have high levels of cholesterol in the blood are more prone to have Alzheimer’s disease later in life,” he says.  Also, people who take statins, a class of drugs that regulate cholesterol levels in the

blood, seem to be protected from getting Alzheimer’s because of these drugs.

“The incidence of Alzheimer’s disease is less in these people,” he says.  “However, we have to keep in mind that statins have more than one effect, and it is not clear whether their protective role in Alzheimer’s is due to reduction of cholesterol levels or through other mechanisms.”

Caffeine, the most commonly ingested psychoactive drug in the world, has been implicated in AD as well, Ghribi says.  Caffeine

has been found to have either a damaging or protective effect on one’s potential to get AD, depending on the amount of consumption.

In collaboration with Geiger, his studies are aimed at increasing scientists’ knowledge of the role that caffeine plays in either increasing or decreasing the type of damage which may lead to AD.

Ghribi, a native of Tunesia, a North African country, came to UND in 2004 after five years as a research assistant professor at the University of Virginia.  He completed his Ph.D. degree in

Paris at the University Rene’ Descartes and took three years’ post-doctoral training at the University of Quebec.

Hope for epilepsy patients

Saobo Lei, Ph.D., is involved in research related to epilepsy, one of the most prevalent diseases in the United States.  Drugs that treat epilepsy, while somewhat effective, produce side effects

and target a limited number of mechanisms.

Exploring new strategies to treat epilepsy is an arduous task, Lei says.  But “we have strong preliminary data” demonstrating that a group of endogenous biological substances, tachykinins,

“significantly increases seizure activities” in rat brain models.

By exploring the involved mechanisms, “we aim our research at finding adequate drugs that interfere with the functions of tachykinins for treating epilepsy,” he says.

Lei completed the doctoral degree at the University of Alberta in Edmonton, Alberta, Canada, in 1997.  He joined UND in 2003.

Identifying disease before symptoms

Thad Rosenberger, Ph.D., is studying biochemical changes in the brain that, if identified early, could lead to development of improved treatment strategies for neurodegenerative diseases.

The research that fascinates Thad Rosenberger, Ph.D., is founded on the premise that in many neurodegenerative diseases, such as Alzheimer’s and multiple sclerosis, biochemical changes occur long before the patients exhibit clinical symptoms.  He feels that if these biochemical changes can be identified early, then treatment

strategies can be developed to prevent the disease and ultimately reduce human suffering.

“Many neurodegenerative disorders have an inflammatory component,” he says. These disorders result in the release of molecules that propagate the disease and disrupt normal brain function.

Rosenberger and his colleagues are determined to shed light on particular inflammatory processes, or “inflammatory signaling cascades,” that occur early in the disease process.  They are analyzing different models of neuroinflammation (an abnormal condition in the brain), using rats, which duplicate many of those aspects found in Alzheimer’s disease, multiple sclerosis, stroke and head injury.

“If we can identify the ‘metabolic hot spots’ before a person shows symptoms of a disease, we may be able to develop therapeutic strategies to reverse the signaling” in order to prevent the disease, he says.  “These studies will allow us to identify those molecules that are involved in the breakdown of the cell and help to develop therapeutic strategies to slow or stop their production.”

Rosenberger, a native of Ohio, earned his doctorate in medical biochemistry, focusing on brain lipid metabolism, at The Ohio State University.  Prior to joining the UND medical school in 2004, he conducted research for five years at the National Institute on Aging, a division of the National Institutes of Health, in Bethesda, MD.  He is senior associate editor of the journal, Lipids.

Calcium’s role in disease progression

Brij Singh, Ph.D., studies the vital mechanism of calcium in the body which, when it doesn’t work properly, leads to diseases such as Parkinson’s disease and Sjorgens syndrome (a salivary gland

dysfunction), as well as cancer.

If that calcium mechanism – governed by a particular protein Singh is studying – gets out of whack, things can go seriously wrong in the body, he notes.  He is pursuing this research

because the mechanism is still incompletely understood even though it is key to many vital body processes.

“When the calcium influx channel gets out of balance – and we’re not sure why that happens – then the body goes into a disease state,” he explains.  “That can be Alzheimer’s, Parkinson’s, heart disease – they’re all related to calcium.”

Singh, who earned his doctoral degree from Bhopal University in India, came to UND in 2003 from the National Institute of Health in Bethesda, MD.

Studying neuronal re-growth

Neuroanatomist John Watt, Ph.D., focuses on the question of how neurons in the brain can re-grow after injury.

In an area of the brain, the hypothalamus, is a type of cell with an unusually high propensity for re-growth in response to injury.  Why this area has such a capability when other central brain regions do not is the compelling question that absorbs the interest of John Watt, Ph.D.

He and his colleagues are analyzing how neurons recover from injury (neurons are similar to electrical conductors that send signals which control bodily functions).  He wants to know if they can re-grow after injury and, if so, how.  His team is focused on elucidating the mechanisms that either promote or prevent survival of injured neurons.

Using rats, his experiments involve damaging the brain, applying a brain chemical called CNTF and then studying the resulting response.  With insights gained from this study, he may be able

to develop intervention strategies to promote survival of injured neurons in other parts of the brain as well.

“The long-term goal is to gain a greater understanding of the mechamisms by which CNTF promotes neuronal survival in the damaged central nervous system,” he says.

His research has important implications for developing improved treatments for diseases such as epilepsy, Huntington’s, Parkinson’s, and ALS (Lou Gehrig’s).  It will also be particularly

valuable for the treatment of people who’ve suffered traumatic brain injury or who experience “phantom limb” pain.

“If we can discover what promotes survival of neurons,” he says, “our findings will allow us to develop intervention strategies that will promote neuro-restorative functions in a variety of neurodegenerative disorders.”

Watt, who joined UND in 2003, earned the doctoral degree in neurobiology from Montana State University in 1993.

-Pamela D. Knudson

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