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UNC Research Day Highlights Human Neurological Disorders

By Eddy Ball
September 2008

James Anderson, M.D., Ph.D.
Department Chair James Anderson, M.D., Ph.D., welcomed visitors from Duke and NIEHS to the 12th annual Research Day, which is held at the beginning of the academic year "to share our science and celebrate the diversity of our research programs" in physiology. (Photo courtesy of Steve McCaw)

Bhat
In his introduction of Piven, Bhat, above, joked that Piven learned only the day before that he and Sisodia had been in different departments at Johns Hopkins University at the same time. (Photo courtesy of Steve McCaw)

Piven
"What has become apparent in the past fifteen years is that autism is a genetic disorder," Piven maintained, "[but] none of the studies performed so far have achieved what is called 'genome-wide significance.'" (Photo courtesy of Steve McCaw)

Gary Bird, Ph.D.
NIEHS Staff Scientist Gary Bird, Ph.D., who is a member of the Calcium Regulation Group, was among the scientists from NIEHS at Piven's talk. (Photo courtesy of Steve McCaw)

Sisodia
"PS1 is at the middle of the story," Sisodia explained. Mutations of PS1 interfere with protein transport and trigger alterations in amyloid metabolism that result in plaque deposition. (Photo courtesy of Steve McCaw)

A contingent of NIEHS scientists joined colleagues from Duke University and the University of North Carolina (UNC) on August 15 for Research Day 2008, hosted at the Chapel Hill Campus by the UNC Department of Cell and Molecular Physiology. The day-long event featured keynote talks on autism and Alzheimer's disease by NIH grantees Joseph Piven, M.D., and Sangram Sisodia, Ph.D., as well as poster sessions for students and postdoctoral trainees in the department (http://www.niehs.nih.gov/)Exit NIEHS.

The morning lecture, "Imaging the Developing Brain in Autism," was by Piven, who is the Sarah Graham Kenan Professor of Psychiatry, Pediatrics and Psychology and director of the Neurodevelopmental Disorders Research Center at UNC. In his introduction, UNC Professor Manzoor Bhat, Ph.D., faculty organizer for the event, described Piven as "a world-renowned authority on autism... [whose] work has been cited thousands of times."

Along with his cutting edge research in imaging the brains of autistic children that was the core of his April lecture (http://www.niehs.nih.gov/news/newsletter/2008/may/brain.cfm) at NIEHS, Piven described efforts to identify children with autism as early as possible and better understand what he described as the spectrum of "autisms" that clinicians encounter. As Piven explained, "I'm really interested in going beyond these kind of crude behavioral phenotypes that we have in autism" to develop quantitative measures to add specificity to the list of criteria in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).

"I often think that you could read DSM-IV on autism," Piven began, "and then sit on a bus next to somebody with autism and you probably wouldn't know it." However, by using a principal components approach, researchers can identify patterns of perception and social orienting that relate to different autism spectrum disorder phenotypes.

By combining brain imaging results with principal component analysis and genetic studies of people with autism, Piven contended, researchers can come closer to sorting through what he called "the laundry list" of candidate genes involved in autism to "disaggregate the syndrome." This approach could help scientists tease apart the substantial heterogeneity in this condition, link genetic abnormalities to specific brain-behavior phenotypes and develop more rationally derived approaches to early intervention.

Sisodia's afternoon talk focused on findings from his group's integrated genetic, neurobiological, molecular and cellular research with an exploration of "Function and Dysfunction of Presenilins in Alzheimer's Disease (AD)." Bhat introduced Sisodia (http://pps.bsd.uchicago.edu/faculty/sangram_sisodia.html)Exit NIEHS with a photo on the screen behind him of the 51-year-old woman who was the first patient described with the disease by German neuropathologist Alois Alzheimer, M.D., in 1907.

Sisodia is the Thomas Reynolds Sr. Family Professor of Neurosciences in the University of Chicago's Department of Neurobiology, director of the Center for Molecular Neurobiology there and a leading expert on the biochemistry and genetics of AD.

The Sisodia group's investigations are focused on understanding the normal biology of proteins involved in the development of Alzheimer's disease, including amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2). The researchers seek to elucidate the molecular and cellular mechanisms by which mutated versions of these proteins promote the amyloid plaque and neurofibrillary tangles that are characteristic of what he predicts will be "an epidemic of staggering proportions" by 2050, when it is estimated that 25 percent of the population will be over 65 years old.

Sisodia's approach in studying these proteins has been to develop cell biological strategies together with specific transgenic mouse models to better understand development of Alzheimer's disease. According to him, these models could be useful for addressing issues relevant to the selective vulnerability of specific CNS systems and the pathophysiological sequelae, providing opportunities to test agents that block these processes.

His group recently reported that enriched environments and exercise modulate the metabolism and deposition of toxic amyloid peptides in the brains of transgenic animals, adding support to the theory that activity, exercise and mental stimulation may be protective, delaying onset of AD by stimulating adult hippocampal neurogenesis.

Catherine Ferguson
NIEHS Summers of Discovery intern Catherine Ferguson, center, a student at Eastern Virginia Medical School, listened intently to Sisodia's talk. Sitting directly behind her were NIEHS Health Science Administrators Kimberly McAllister, Ph.D., left, and Annette Kirshner, Ph.D., right. (Photo courtesy of Steve McCaw)

Expanding the Autism Data Base

Toward the end of his talk, Piven lamented a common shortcoming of autism research. "One of the things that bedevils this research," he said, "is the sample size."

That situation could begin to change in 2009 with enrollment of subjects in a new large-scale epidemiological study of gene-environment interactions being supported by NIEHS grants managed by Health Science Administrator Cindy Lawler, Ph.D. Piven said that he will be pairing up with the Early Autism Risk Longitudinal Investigation (EARLI) Network (http://publichealth.drexel.edu/News/SPH_AWARDED_14M_NIH_GRANT_FOR_AUTISM_RESEARCH/586/)Exit NIEHS, a ten-year study of mothers of autistic children and their newborn siblings headed by Principal Investigator Craig J. Newschaffer, Ph.D., of Drexel University.

The network plans to implement a core epidemiologic data collection protocol focusing on prospective documentation of exogenous exposures, continuous autistic spectrum disorder (ASD) behavioral domains during pregnancy and early life, collection and banking of biological samples and follow-up of 1,200 newborn siblings through 36 months of age.

"The focus of their [EARLI] study is environmental," Piven said. "We're going to join up with them and add a genetics component with genome-wide data and look at the relationship with environmental factors."

With this increase in the data researchers need to truly understand the various linkages among genes, behavior and biology, investigators may be able to identify genetic, biological and family pedigree predictors of autism much earlier than the six-month point where Piven has found brain enlargement in autistic children.

 


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