Archived | 2008 Pilot Awards (Summer) | Circa 2008 #NotAnAutisticAlly

2008 Environmental Factors Awards
2008 Basic and Clinical Awards (Winter)
2008 Basic and Clinical Awards (Summer)
2008 Epidemiology Awards
2008 Fellowships
2008 High Risk, High Impact Projects
2008 Pilot Awards (Winter)
2008 Pilot Awards (Summer)
2008 Treatment Awards

Matthew Belmonte, Ph.D.
Cornell University
$119,968 for 2 years

Video game environments for the integrative study of perception, attention and social cognition in autism and autism sibs

Autism’s social and communicative deficits are its most obvious and debilitating symptoms. Less appreciated are the lower-level, non-social symptoms, such as enhanced sensory perception, narrow and inflexible attention, and executive abnormalities such as difficulties in planning and goal-oriented behavior. Both higher-level and lower-level symptoms of autism may be explained by changes in neural connectivity in the brains of autistic individuals. Neurons communicate to each via both long-range and short-range neural connections. In this study, Dr. Belmonte and colleagues will test the hypothesis that the range of symptoms seen in autism can be explained by abnormally strong short-range connections within brain regions, and abnormally weak long-range connections between brain regions. These researchers hypothesize that social and communicative deficits seen in autism are due to weakening of the long-range connections between brain regions, which are necessary to coordinate the activities of these regions.

This study will use EEG to measure brain activity in autistic children and their siblings, as well as a control group of normal children. Brain activity will be measured both within and between brain regions while the subjects play video games with embedded tests for both high-level and low-level functions, such as attention, executive function, perception, and social cognition. Computational analysis of the activity measured will allow researchers to determine the relative strength of neural connections in different subjects while performing different types of tasks.

This research will evaluate a unified hypothesis of brain dysfunction in autism, which may lead to a better understanding of the neural pathways underlying the symptoms of autism.

Ellen Carpenter, Ph.D.
University of California, Los Angeles
$60,000 for 1 year

Genetic and epigenetic interactions in a mouse model for autism

Autism likely results from a combination of genetic and environmental factors, and particular genetic variations may make an individual more sensitive to environmental factors. In this study, Dr. Carpenter and colleagues will examine the interaction between a specific gene and an environmental factor in the development of autistic-like behaviors in a mouse model. The gene to be examined in the present study, the reelin gene, is a candidate genetic factor for autism, and is important for the development of the cerebral cortex and cerebellum. Mice with reduced levels of expression of this gene have neurodevelopmental defects which result in behavioral abnormalities. 

This research will examine the effects of an environmental factor hypothesized to be a risk factor for autism (organophosphate exposure during the prenatal period) on the development of autistic behaviors in mice which express low levels of the protein encoded by the reelin gene. It will also determine whether reduced reelin expression in combination with organophosphate exposure leads to changes in the anatomy of brain regions associated with these behaviors. 

This research will determine whether the reelin gene and organophosphate exposure may be risk factors for autism, and whether genetic variation in the reelin gene increases developmental sensitivity to organophosphates.

Shawn Christ, Ph.D.
University of Missouri-Columbia
$120,000 for 2 years

The neural correlates of transient and sustained executive control in children with autism spectrum disorder

Autism spectrum disorder (ASD) is often associated with impairments in executive control, the neural activities that allow for and produce goal-directed actions. The present study will use structural and functional brain imaging to more characterize brain activity in autistic adolescents during tasks which involve executive control, and to more fully define how executive control is affected in ASD.

Functional magnetic resonance imaging (fMRI) will be used to visualize regional brain activities in 40 high-functioning adolescents with ASD and an age-matched control group during their performance of an executive control task. The resulting data will be used to determine whether the impairments experienced by individuals with ASD are characterized by brain activity typical of a failure to maintain an appropriate overall approach to the task at hand, or a failure of moment-by-moment implementation of executive control. As well, brain regions demonstrating abnormal activation in ASD individuals during executive control tasks will be further examined for atypical structure and connectivity to other parts of the brain.

Determining the aspects of executive control and associated brain structures that are affected in ASD will be of use in the design and selection of appropriate behavioral therapies .

Thomas Conturo, M.D., Ph.D.
Washington University School of Medicine
$119,963 for 2 years

Analysis of brain microstructure in autism using novel diffusion MRI approaches

There is increasing evidence that brain regions of autistic individuals have altered neural connectivity between different brain regions. Preliminary work has shown that autistic brains tend to have changes in the structure and anatomy of the white matter tracts that carry neural information between brain regions. The methods commonly used to visualize the anatomy of white matter, diffusion tensor MRI and diffusion-tensor tracking, do not provide a level of microscopic detail which would allow researchers to determine the underlying biological causes of the structural abnormalities observed in white matter.

In the present study, Dr. Conturo and colleagues will develop new diffusion MRI techniques which will allow them to examine the microscopic structure of white matter tracts. They will combine existing diffusion MRI methods with novel computational approaches aimed at determining the cellular basis of white matter abnormalities, and apply these new methods to examining the brains of individuals with autism.

This research may help to define the underlying cellular disturbances which result in abnormal white matter tracts in autism, as well as provide new diagnostic tools for neurodevelopmental disorders.

Lisa Croen, Ph.D.
Kaiser Permanente Division of Research
$120,000 for 2 years

Early Biologic Markers for Autism

The prenatal period is a crucial period of brain development, and therefore the maternal environment can have an impact on fetal neurodevelopment. In particular, proteins of the maternal immune system during pregnancy may be able to affect the development of the fetal brain, as these proteins can cross the placenta and enter fetal tissues. Preliminary results have provided evidence that elevated levels of certain immune system proteins in the blood of pregnant women may be associated with an increased risk of autism in their children. During mid-pregnancy, these researchers found elevated levels of specific cytokines (proteins which attract immune cells to sites of infection), and the presence of autoantibodies, proteins which can recognize and bind to cells and proteins in the fetus. Maternal cytokines and autoantiodies could affect fetal brain development by binding and signaling to cells and proteins in the fetal brain, or they could affect the immune system of the fetus.

These researchers will extend their preliminary data by conducting a large controlled study on the association between levels of autoantibodies and cytokines in maternal blood samples during mid-pregnancy with the associated risks of autism and mental retardation in the offspring. 1200 mother-child pairs will be included in this study, as well as 200 siblings of autistic and mentally retarded children. These data will determine whether inappropriate activation of the immune system during pregnancy is associated with an increased risk of neurodevelopmental problems.

The results from this study should contribute to our understanding of the impact of the maternal environment on fetal development, and its contribution to autism. It may also provide new, early tests for an increased risk of autism. (Co-sponsor: The Higgins Family Charitable Foundation)

Robert Fujinami, Ph.D.
University of Utah
$119,991 for 2 years

Deriving neuroprogenitor cells from peripheral blood of individuals with autism

The physical examination of neurological changes in individuals with autism has been made difficult by the necessity of obtaining brain tissue in a timely manner from individuals who have died. Being able to obtain tissue from autistic patients in a noninvasive manner would enhance the ability of researchers to study the cellular changes which occur in autistic brains. A potential technique to circumvent this problem is the use of peripheral mononuclear blood cells (or PMBCs), which are similar to stem cells and can be obtained from blood samples. In the laboratory, PMBCs can be differentiated into multiple types of cells, including neurons. PMBCs derived from the blood of autistic individuals might provide a useful method of examining the effects of genotype on the differentiation and function of neurons.

In this study, Dr. Fujinami and colleagues will test the feasibility of making neurons from PMBCs obtained from autistic individuals. If neurons can be derived from these cells, they will examine the characteristics of the neurons obtained from autistic individuals to determine whether they differ from those derived from typical individuals. Neurons from autistic individuals, for example, might express different genes than those from typical individuals, or survive at different rates.

This research could provide a powerful new tool to study neuronal function in autism, and supplement the data obtained from traditional postmortem analyses.

Cecilia Giulivi, Ph.D.
University of Californa, Davis
$120,000 for 2 years

Is autism a mitochondrial disease?

Recent studies have suggested that autism may be associated with perturbations in cellular energy metabolism. The brain is a highly energy-dependent tissue, and is very sensitive to changes in energy metabolism. The underlying cause of the changes in energy metabolism seen in autism is not known; however, it is hypothesized that it involves a dysfunction in mitochondria, the cellular structures which are responsible for metabolizing nutrients to energy that can be used by the cell.

Dr. Giulivi and colleagues will test the hypothesis that mitochondrial dysfunction is associated with altered expression of the gene PTEN. This gene has been connected to autism-like symptoms and neurodevelopmental disorders, and may also be involved in mitochondrial function. In the present study, mitochondria will be systematically examined in mice engineered to lack the PTEN gene. This research will clarify the aspects of mitochondrial function and energy metabolism which are disrupted in the absence of this gene.

Results from these experiments should enhance the understanding of the connection between energy metabolism, mitochondrial dysfunction, and autism, and may lead to new diagnostic or treatment methods.

Walter Kaufmann, M.D.
Kennedy Krieger Institute
$120,000 for 2 years

Autism spectrum disorder in Down syndrome: a model of repetitive and stereotypic behavior for idiopathic ASD

Down syndrome is the most common genetic disorder associated with neurobehavioral problems, and many children with Down syndrome have clinically significant behavioral problems, including autism spectrum disorders (ASDs). Preliminary research from Dr. Kaufmann’s lab has shown that children with both Down syndrome and ASD have a unique profile of autistic core symptoms, including severe stereotypies (repetitive movements) which are distinct from more common movement disorders associated with Down syndrome.

The present study will test and further confirm the hypothesis that the diagnosis of Down syndrome plus ASD is associated with both a unique behavioral profile and distinctive genetic characteristics. 70 boys with Down syndrome, with and without ASD, will be recruited for this study. Subjects will be evaluated for behavioral problems, including stereotypies and developmental regression, using methods of analysis which have not yet been applied to studying behavior in Down syndrome.

This research may lead to improved diagnoses and treatment of Down syndrome plus ASD, and provide insight into various behavioral aspects of ASDs.

Naila Khan, M.D.
Bangladesh Protibondhi Foundation
$59,966 for 1 year

Scales, procedures, and intervention programs for estimating the prevalence of childhood disability and autism in Bangladesh

The diagnosis of autism spectrum disorders (ASDs) has increased six-fold over the past decade in Bangladesh. However, this resource-poor country has no comprehensive early screening system for neurodevelopmental disorders. Studies in western countries have suggested that estimates of the prevalence of ASDs may be too low unless children with a range of neurodevelopmental problems are assessed, as the early signs of autism are so variable. A

The purpose of this study is to standardize tools for the identification of neurodevelopmental problems, including ASDs, in 0 to 5-year-old children in Bangladesh. These tools will be designed for use by community workers in both rural and urban communities. This study will develop simple epidemiological tools for estimating the prevalence of ASDs. These tools will be linked with facilitated access to services and early intervention for families.

The procedures developed in this study will be a starting point for a full-scale study of the prevalence of ASD in Bangladesh, and may be applicable for use in other developing countries.

Mark Lewis, M.D.
University of Florida
$120,000 for 2 years

The genetics of restricted, repetitive behavior: an inbred mouse model

Characteristic features of autism spectrum disorders (ASDs) are restricted, repetitive behaviors (RRBs) such as stereotyped movements, compulsions or rituals, and a resistance to change and restricted interests. Little is known about the genetic factors involved in repetitive behaviors, and appropriate animal models for these behaviors could be of use in identifying gene variants associated with RRBs.

In this study, Dr. Lewis and colleagues will develop a mouse model of RRBs which will allow them to identify variations in the mouse genome associated with these behaviors. These researchers have previously identified an inbred mouse line that displays both repetitive behaviors (jumping, flipping, and weaving) and restricted behaviors (reduced exploration of the environment). The present research will examine the genetic basis of these behaviors, characterizing the regions of genomic DNA which are associated with these behaviors. This may lead to the identification of gene variants which are involved in the development of RRBs.

The examination of genetic variation in a mouse model of RRB should have direct value for clinical genetic studies of ASDs, and aid in our understanding of the underlying biology of this diagnostic feature of autism.

Antonio Persico, M.D.
University Campus Bio-Medico
$120,000 for 2 years

Identification and functional characterization of gene variants

The genetic predisposition to autism is likely to be conferred by multiple genes and gene variants. As there is a strong familial component to autism, even the unaffected siblings of autistic children may to carry multiple vulnerability genes that are also carried by their autistic siblings. It is hypothesized that unaffected siblings may therefore have additional, protective genetic variants, which confer resistance to the development of autism, and which are missing in their autism-affected siblings.

Previous research from the Persico laboratory has identified two gene loci as candidate protective genes in unaffected siblings of children with autism. In the present study, these researchers will use DNA sequencing to characterize genetic variation at these loci. Next, they will determine the functional consequences of the expression of these protective gene variants using in vitro techniques.

Identification and characterization of protective gene variants will be a powerful strategy in identifying therapeutic targets which may prevent the negative effects of the vulnerability genes.

Mikhail Pletnikov, M.D., Ph.D.
Johns Hopkins University School of Medicine
$120,000 for 2 years

Gene-environment interactions in the pathogenesis of autism-like neurodevelopmental damage: a mouse model

Autism likely results from a combination of genetic and environmental factors, as particular genetic variations may make an individual more sensitive to environmental factors. The present study will examine the interaction between a specific gene and an environmental factor, both known to confer risk of neurodevelopmental problems. The gene under study is DISC1, which is located in a region of the human genome likely to harbor an autism susceptibility gene. Mice with mutant versions of this gene have a predisposition to neurodevelopmental problems, which may be exacerbated or influenced by environmental factors.

One prenatal environmental factor that may modulate vulnerability to autism in the prenatal period is the maternal immune response. In this study, Dr. Pletnikov and colleagues will examine the interaction between mutations in DISC1 and the maternal immune response. They will administer a compound which mimics important aspects of the maternal immune response to viral infections to pregnant mice which harbor mutant versions of DISC1. They will examine neural development and autistic-like behaviors in the offspring of mice given the immune stimulus during pregnancy to test the hypothesis that the environmental challenge (immune activation) will exacerbate the alterations in brain development and behavior seen in DISC1 mutants,.

This research may identify molecular mechanisms mediating gene-environment interactions important for neurodevelopment, which would be therefore be novel targets for the development of drugs to prevent or treat neurodevelopmental problems.

Diana Robins, Ph.D.
Georgia State University
$119,966 for 2 years

Psychophysiological mechanism of emotion expression

Individuals with autism spectrum disorders (ASDs) often have difficulty perceiving emotional cues such as facial expression, tone of voice, or body posture, which contributes to impairments in social skills. Previous research has shown that while typically developing individuals automatically mimic facial expressions when viewing pictures of emotional facial expressions, individuals with ASD tend not to respond in this way. 

The present study will examine automatic facial mimicry in 20 individuals with ASD in response to both visual and audio emotional cues. Rather than still photos, more realistic audio-video cues will be used. Facial movement and expression in response to cues will be measured using sensors attached to the face. Researchers will determine whether deficits in automatic facial mimicry in correlate with emotion perception and social engagement. 

This research will clarify whether facial mimicry is involved in emotional perception in, and may contribute to our understanding of deficits in social skills in ASD.

Susan Santangelo, Ph.D.
Massachusetts General Hospital
$120,000 for 2 years

Investigation of genes involved in synaptic plasticity in Iranian families with ASD

Autism spectrum disorders (ASDs) are thought to involve changes in synaptic plasticity, or the remodeling of neural connections during development. Synaptic plasticity is crucial for learning and memory as well as the development of brain structures. Mutations in genes associated with a particular modulator of synaptic plasticity, the NMDA neurotransmitter receptor, have been shown to contribute to mental retardation, fragile X syndrome, and tuberous sclerosis complex, all of which are conditions associated with ASDs. These genes might therefore contribute to ASD by disrupting a molecular pathway common to all of these disorders, and affecting synaptic plasticity.

In this study, six genes involved in NMDA receptor-dependent synaptic plasticity will be examined in a study of Iranian families with ASD. The sequence of these genes will be examined in DNA from related individuals, both typical and with ASD, to determine whether sequence variations in any of these genes are associated with ASD.

Determining whether genes involved in synaptic plasticity play a role in ASD may identify new gene variants conferring a risk of autism, as well as further our understanding of synaptic dysfunction in autism.

Zohreh Talebizadeh, Ph.D.
The Children’s Mercy Hospital
$119,982 for 2 years

Potential role of noncoding RNAs in autism

Genetic predisposition to autism may involve both differences in the coding regions of DNA (genomic regions encoding RNAs which are eventually translated into proteins) and changes in the regulation of gene expression, though the coding regions of DNA are unaffected. A recently discovered mechanism for the regulation of gene expression is non-coding RNAs (RNAs which do not get translated into proteins). Non-coding RNAs may regulate the translation of other RNAs to proteins. Changes in expression of these non-coding RNAs could potentially be involved in the development of autism.

This study aims to characterize the non-coding RNAs present in autistic individuals compared to normal individuals. Researchers will use microarray technology capable of measuring the levels of thousands of individual RNAs to identify which non-coding RNAs are expressed at different levels in blood cells from autistic versus non-autistic subjects.

Examining non-coding RNAs is a novel approach to discovering the biological mechanisms underlying autism, and may identify novel drug targets for the treatment and prevention of autism.

Jeremy Veenstra-VanderWeele, M.D.
Vanderbilt University
$120,000 for 2 years

Mouse genetic model of a dysregulated serotonin transporter variant associated with autism

Elevated serotonin levels are frequently found to be associated with autism. Serotonin levels may be regulated by the serotonin transporter (encoded by the SERT gene), which is responsible for transporting serotonin to the inside of cells. A rare mutation in the SERT gene has been previously identified in several autistic individuals. While many mutations inactivate genes, this particular mutation seems to increase rather than decrease the activity of the serotonin transporter.

To examine the functional and behavioral consequences of this mutation in the SERT gene, the present study will engineer mice to carry the mutation. This study will focus on behavioral analyses to determine whether the mutation found in humans will cause autistic-like behaviors in a mouse model. These behavioral analyses will provide a basis for the future exploration of the molecular basis of autistic behaviors related to the serotonin transporter.

This research should help clarify the role of variation in the serotonin transporter gene in the development of autistic-like behaviors, and may suggest novel therapies for people who have this particular mutation.

Tao Wang, M.D., Ph.D.
Johns Hopkins University School of Medicine
$120,000 for 2 years

Understanding glutamate signaling defects in autism spectrum disorders

A disruption of the balance between the activity of excitatory neurotransmitters (which increase neural activity) and inhibitory neurotransmitters (which decrease neural activity) may be involved in autism. The principal excitatory neurotransmitter, glutamate, is counteracted by the activity of inhibitory neurotransmitters. Disregulation of either neurotransmitter system results in abnormal levels of neural activity. Mutations in genes involved in glutamate neurotransmission could lead to this kind of imbalance, and therefore confer a risk of autism.

In the present study, Dr. Wang and colleagues will conduct a high-throughput genetic screen in a cohort of autistic patients, looking for DNA sequence variants in 38 genes known to be involved in glutamate neurotransmission. If the hypothesis that glutamate is involved in autism is correct, they expect to find multiple rare sequence variants of these genes in autistic patients, compared to a non-autistic control sample.

This research may clarify the role of glutamate in autism, as well as identify new genetic risk factors and potential drug targets for the treatment and prevention of autism.

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