Autism and Angelman syndrome targeted in 2016 Discovery Grants

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The Michael C. Walther II Discovery Grant and two Nicholas Hobbs Discovery Grants have been awarded for 2016-17, announced Elisabeth Dykens, Ph.D., Vanderbilt Kennedy Center (VKC) director and Annette Schaffer Eskind Chair.

Discovery Grants are an annual VKC grant program open to VKC investigators and members. Their purpose is to support multidisciplinary, innovative preclinical or clinical pilot studies in preparation for submitting competitive grant applications to federal agencies or private foundations. The program is made possible by the generous gifts of individual donors for named grants and by members of the Nicholas Hobbs Society, the VKC donor society. For 2016-17, grant awards ranged from $25,000 to $30,000.

“We are enormously grateful to Mike Walther and all our Nicholas Hobbs Society members for their generosity, which makes these innovative pilot grants possible,” Dykens said.

“We are privileged to support all these endeavors,” said Karoly Mirnics, M.D., Ph.D., VKC associate director, James G. Blakemore Chair and Vice Chair for Research in Psychiatry. “We expect that this exploratory research will attract further attention and research funding from federal agencies.”

Walther Discovery Grant-—Assessing a telehealth autism service model

“The Walther Discovery Grant in the area of autism spectrum disorder (ASD) was awarded to Pablo Juárez, TRIAD director, and an exceptional team of TRIAD researchers,” Dykens said. “Their project addresses the crucial need for diagnostic and early intervention services for children with ASD in rural areas, where services and resources are most often scarce.”

The Michael C. Walther II Discovery Grant was established by Michael Walther, a Vanderbilt alumnus, to advance innovative research with the potential to help countless children and adults with developmental disorders.

In this project, “Assessing Feasibility and the Impact of Telemedicine-Based Early Intervention Services,” the TRIAD research team will conduct a pilot trial of an innovative, rural telemedicine service program that can be leveraged to pursue a larger federal service system intervention grant over time. They will evaluate a telehealth mechanism as compared to “business as usual” for providing early diagnostic services as well as medical/psychiatric consultation for children with ASD in rural areas of Tennessee.

“We will compare two service delivery models,” said Juárez. “One is a telemedicine model and the other is a more traditional in-person model. Within both groups, Vanderbilt behavior analysts will partner with Vanderbilt psychologists and physicians to identify needs of families and their providers, as well as train caregivers and providers to address these needs using evidence-based practices for young children with ASD.”

The research team will assess several aspects of each service delivery model, including feasibility of implementation, provider and caregiver satisfaction, clinical impact of services, system acceptance, and cost-effectiveness.

“We anticipate that telemedicine services are likely to be more cost-effective than direct, in-person services, and that they will promote overall service accessibility for families who may otherwise experience very limited access to quality diagnostic, behavioral, and medical services,” said Juárez.

In addition to Juárez, M.Ed., BCBA (Pediatrics, Psychiatry) as principal investigator, the TRIAD research team includes Kevin Sanders, M.D. (Clinical Psychiatry), co-investigator; Zachary Warren, Ph.D. (Pediatrics, Psychiatry, Special Education), co-investigator; and Alacia Stainbrook, Ph.D., BCBA-D, (Pediatrics), co-investigator and project coordinator.

Nicholas Hobbs Discovery Grants—-Understanding Mechanisms Underlying ASD and Angelman Syndrome

Two Nicholas Hobbs Discovery Grants were awarded to VKC neuroscientists who use mouse models to investigate basic mechanisms underlying ASD and Angelman syndrome, respectively.

Investigating gene-related mechanisms in autism spectrum disorder

Mutations in multiple human genes have been linked to ASD. Many of these genes encode proteins that play important roles in regulating synaptic communication among neurons in the brain. Studies in animal models have shown that ASD-linked mutations cause changes in the size, number and/or function of synapses in the brain, as well as behavioral changes that are believed to resemble some symptoms of ASD. However, it is unclear how the direct effects of such mutation on the primary functions of these diverse proteins are linked to the core intracellular processes that are presumed to underlie the development of ASD symptoms. Investigators hope that careful characterization of ASD-linked mutations in additional genes and comparisons among animal models will lead to the development of a more integrated understanding of ASD mechanisms.

Roger Colbran, Ph.D., was awarded a Hobbs Discovery grant, “CaMKII in Autism Spectrum Disorder,” to characterize a newly created mouse that carries a mutation on the gene encoding the highly abundant neuronal α isoform of the enzyme, calcium/calmodulin-dependent protein kinase II (CaMKIIα). A large genetic study of 2,500 families detected this de novo mutation in a single individual with ASD, but not in a sibling or in either parent. Initial studies in the Colbran lab have found biochemically that this mutation essentially inactivates CaMKIIα and that the mutated CaMKIIα reduces the number and function of synapses in neurons that have been cultured in vitro. The Hobbs Discovery grant will support the initial biochemical, electrophysiological, and behavioral analyses of the new mice carrying this mutation. The data from these studies will provide critical support for future applications for major extramural funding to support detailed follow-up studies that provide new insights into the molecular mechanisms underlying ASD.

“Cellular mechanisms that link the specific primary effects of genetic mutations to core processes that presumably underlie ASD symptoms remain poorly understood, and this groundbreaking research tries to shed light on such processes,” Mirnics said.

In addition to Colbran (Molecular Physiology & Biophysics) as principal investigator, the research team includes James Bodfish, Ph.D. (Hearing and Speech Sciences), co-investigator; James Sutcliffe, Ph.D. (Molecular Physiology & Biophysics), co-investigator; and Jason Stephenson (Molecular Physiology & Biophysics), postdoctoral researcher.

Rescue of behavioral circadian phenotypes in Angelman syndrome model mice

Angelman syndrome (AS) is a disorder characterized by cognitive/developmental delays, speech impairment, sleep disorders, seizures, and motor difficulties. The expression level of the Ube3a gene is crucial for normal neurodevelopment. For example, reduced dosage of Ube3a leads to Angelman syndrome and increased dosage/activity can result in autism.

Carl Johnson, Ph.D., and colleagues recently reported that the effective gene dosage of this Ube3a gene also regulates fundamental properties of the circadian clock system in mammals. Circadian (daily) rhythms regulate myriad behavioral and molecular processes including locomotor activity, sleep timing, feeding behavior, metabolism, and gene expression. Therefore, the level of expression of Ube3a is critical for normal cognitive development. The thesis of this project is that balanced expression of Ube3a is key for robust circadian rhythmicity as well.

With the Hobbs Discovery grant, Johnson will test treatments to identify the first pharmacological rescue of behavioral phenotypes affected by AS. This project represents a novel area of investigation that has the potential to enhance health-related research by identifying treatments that ameliorate the circadian disorders of Ube3a imprinting in mouse models. The long-term goal is to understand the Ube3a connection between the debilitating neurodevelopmental disorder AS and fundamental circadian organization in this fascinating–-and clinically relevant–-example of gene X environment interaction.

“This project represents a novel area of investigation that has the potential to enhance health-related research by identifying treatments that ameliorate the circadian disorders across multiple neurodevelopmental disorders.” said Mirnics.

In addition to Carl Johnson, Ph.D. (Biological Sciences) as principal investigator, Rebecca Ihrie, Ph.D. (Cancer Biology) is co-investigator.

Jan Rosemergy, Ph.D., is VKC deputy director and director of Communications and Dissemination.

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