Archived | Autism Speaks: 2008 Fellowship Grants | 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

Christin Collins, Ph.D.
Children’s Hospital Boston
$102,000 for 2 years

Gene Expression Profiling of Autism Spectrum Disorders

Autism Spectrum Disorders (ASDs) are likely caused by interactions between genetic and environmental factors which result in changes in neural development and activity. These changes might be associated with differences in the levels of expression of multiple different genes in both the nervous system and in peripheral blood cells.

Identifying reproducible changes in gene expression levels in individuals with ASDs would be a valuable tool both for understanding the molecular basis of these disorders and in developing earlier and more accurate diagnostic tests. In the proposed study, Dr. Collins will examine gene expression profiles in individuals with ASDs using microarray technology, a technique used to measure the levels of expression of thousands of genes simultaneously.

Gene expression in peripheral blood from ASD patients will be compared to that of healthy controls, and genes expressed at either higher or lower levels in the ASD patients will be identified. This approach may identify novel genes which are misregulated in autism, as well as provide the basis for the development of newer, more sensitive diagnostic tools for this disorder. 

Deanna Greene
University of California Los Angeles
$56,000 for 2 years

Neural Basis of Socially Driven Attention in Children with Autism

People with autism often have difficulties in shifting their attention in response to social cues. In typical individuals, social cues such as the direction of another person’s eye gaze cause automatic shifts in attention. It is unclear whether the impairment in attention shifting seen in autism is due to the social nature of the cue or to a more general problem in automatically shifting attention.

The present study will begin to address this important question. Children with and without autism will perform a well-established task for measuring attention shifts in response to different cues. The cues will either be social in nature (eyes looking left or right) or nonsocial (arrows pointing left or right).

The task will be performed while the subjects undergo functional magnetic resonance imaging (fMRI), a technique used to image neural activity in specific regions of the brain. These experiments will determine the exact nature of the impairment in attention shifting, as well as provide information about the brain regions involved in this impairment.

This research will advance our understanding of the neural basis of attention shifting problems in individuals with autism, which may provide a foundation for the development of interventions to treat this aspect of social impairment.

Ravinesh Kumar, Ph.D.
University of Chicago
$99,000 for 2 years

Genomic Imbalances in Autism

Several lines of evidence support a major genetic contribution to autism, including large visible chromosomal rearrangements detected in 3-7% of autism patients. However, little is known about the role of smaller, submicroscopic chromosomal abnormalities that are not readily detectable using traditional methods.

Using a novel, state-of-the-art approach called array comparative genomic hybridization (aCGH), researchers have recently discovered a small deletion containing 24 genes on Chromosome 16p11.2 that represents one of the most frequent chromosomal abnormalities described in autism to date.

In the proposed study, Dr. Kumar will extend this finding by selecting the most promising candidate genes for involvement in autism from this newly identified 16p11.2 chromosomal region. These genes will be examined in patients to search for the presence of mutations significantly associated with autism. As well, aCGH will be used to identify additional novel submicroscopic chromosomal rearrangements in a sample of approximately 300 autism patients who have not been previously tested for these abnormalities.

The identification of novel candidate genes and chromosomal abnormalities in autism patients will further our understanding of the genetic factors conferring risk of autism, and may improve the accuracy of diagnostic tests for this disorder.

Jillian Lee
University of Michigan, Ann Arbor
$56,000 for 2 years

fMRI evidence of genetic influence on rigidity in ASD

A hallmark symptom of autism is rigidity, or difficulty in adapting to changing environments. This adaptive ability is also known as cognitive flexibility. In autistic individuals, brain regions which control cognitive flexibility may be abnormal, but research has yet to directly link abnormal activity in these brain regions to rigidity symptoms.

Rigidity symptoms may also have a genetic component, as genetic variation could affect cognitive flexibility and brain function. Genes linked to autism are candidates for being involved in these processes. The present study will examine the association between cognitive flexibility, pathways of neural activity, and a particular autism-linked gene, 5-HTTLPR, which is involved in signaling by the neurotransmitter serotonin. Using functional magnetic resonance imaging (fMRI), the predoctoral fellow will test the hypothesis that variation in the 5-HTTLPR gene is related to rigidity symptoms.

She will use fMRI to look at the patterns of neural activity while ASD individuals perform a task measuring cognitive flexibility. The subjects will include people with multiple different alleles of the 5-HTTPLPR gene. This will determine whether different 5-HTTLPR genotypes are associated with abnormal brain activation patterns during cognitive flexibility tasks, or with the severity of rigidity symptoms.

This research may identify genetically influenced neural and cognitive abnormalities affecting cognitive flexibility that could potentially be targeted by therapies to alleviate symptoms of rigidity.

Katherine Meyer
Michigan State University
$56,000 for 2 years

A Sibling Mediated Imitation Intervention for Young Children with Autism

Children with autism have significant difficulties with social communication, and have particular trouble forming relationships with other children. Social skills interventions are often limited in their ability to teach social interaction skills that can generalize to novel contexts.

Given that typically developing siblings spend a significant amount of time with their sibling with autism in a variety of contexts, teaching older siblings to provide intervention to their younger sibling with autism may be an effective method for promoting social skills that can be generalized across social contexts. Sibling-mediated intervention may also have positive effects for the typically developing sibling.

Previous research has suggested that reciprocal imitation, in which partners imitate one another in extended turn-taking sequences, is a promising intervention strategy for children with autism. This study will evaluate the efficacy of sibling-implemented Reciprocal Imitation Training (RIT), a naturalistic imitation intervention designed to teach reciprocal imitation skills to children with autism.

Researchers will examine whether siblings are able to learn the intervention, and whether the intervention efficiently increases the social-communicative skills in the children with autism. This study will evaluate the effectiveness of both a specific intervention (RIT) and intervention approach (sibling-mediated intervention), which may prove useful in developing social skills in children with autism.

Akiko Mizuno
Carnegie Mellon University
$56,000 for 2 years

Linguistic Perspective-Taking in Adults with High-Functioning Autism: Investigation of the Mirror Neuron System

The mirror neuron system (MNS) is thought to be a part of the brain that is important for understanding the behaviors and intentions of others. Because autistic people generally have difficulties in understanding other people’s intentions, it is hypothesized that the MNS may be dysfunctional in autism.

To understand another person’s intentions, we put ourselves in their shoes; this process is called perspective-taking. An example of perspective-taking is the use of personal pronouns, because pronouns such as ‘I’ and ‘you’ alternate to whom they refer according to the situation.

Young children with autism have been found to have difficulty in using pronouns properly. The present study will examine the activity of the MNS in autistic adults while they are engaged in a perspective-taking task involving the use of pronouns.

Using functional magnetic resonance imaging (fMRI), the MNS will be observed during this task to determine whether abnormal activation in the autistic brain is associated with difficulties in perspective-taking. Determining whether the mirror neuron system is involved in linguistic perspective-taking in autism may provide insight into the neurological basis of social deficits in autism.

Leena Mohapatra
University of Miami
$56,000 for 2 years

Cognitive Control and Social Engagement Among Younger Siblings of Children with Autism

Younger siblings of children with autism are at higher risk for developing autism, and although they may not meet the diagnostic criteria for autism sometimes display subtle variants of the social, emotional, and cognitive deficits seen in autism.

These children are therefore a valuable population in the study of the mechanisms of atypical development and behavior in autism. This study is designed to examine the associations between early cognitive and attentional processes and socialization skills among preschool-aged younger siblings of children with autism. The neural mechanisms of attentional control are especially important to understand, as it appears that these skills can be changed through behavioral training.

Working with siblings of autistic children, these experiments will test the hypothesis that the greater amount of cognitive control and attention exhibited by a child, the more self-regulatory and prosocial behaviors the child will exhibit when they are socially engaged. To measure attention and cognitive control (the effort it takes to inhibit a response), the predoctoral fellow will use EEG/ERP to measure brain activity in regions known to be involved in these processes.

The children will also be tested for various behavioral aspects of social engagement in order to determine whether there is an association between these behaviors and the degree of cognitive and attention control. Understanding the relationship between attention control and social behaviors may help in our ability to improve interventions directed at these processes.

Matthew Mosconi, Ph.D.
University of Illinois, Chicago
$95,000 for 2 years

FMRI Studies of Cerebellar Functioning in Autism

Autism is a pervasive neurodevelopmental disorder in which multiple parts of the brain are affected. The most consistent neuropathological finding in autism is a reduced number of Purkinje cells, large neurons located in the cerebellum.

The cerebellum is a part of the brain responsible for motor coordination, but how the cerebellar abnormalities found in autism affect behavior is not well understood. Recent preliminary data has suggested that decreased activity in particular regions of the cerebellum of autistic patients is associated with difficulties in controlling manual force and in visual pursuit systems (i.e., visual tracking of moving objects).

In this study, Dr. Mosconi will examine the role of the cerebellum in controlling and modulating sensorimotor performance for eye and hand movements using functional magnetic resonance imaging (fMRI). FMRI is a technique used to visualize the activity of neural circuits. In this study, the focus will be on patterns of neural activity in the cerebellum during the performance of visual and sensorimotor tasks.

The brains of adults with autism and age-matched controls will be imaged by fMRI while they perform a series of visual pursuit and grip force control tasks. The fMRI data should show whether differences in neural activity in the cerebellum of autistic patients correlate with specific difficulties in sensorimotor performance.

This study may help us to understand the significance of the cerebellar abnormalities seen in autistic brains, as well as shed light on the role of the cerebellum in sensorimotor performance. 

Nathan Okerlund
University of California San Francisco
$56,000 for 2 years

Roles of Wnt Signaling/Scaffolding Molecules in Autism

Autism spectrum disorders (ASDs) are thought to arise from disruptions in brain development. A crucial biochemical pathway involved in neurodevelopment is the Wnt signaling pathway, which can affect both brain size and organization.

Misregulation of Wnt signaling is therefore a potential cause of ASDs, and mutations in genes that affect the Wnt pathway might confer a risk of ASDs. Recently, a family was discovered in which two children diagnosed with ASD harbored a mutation in the Dact1 gene, which is involved in Wnt signaling. The present study will investigate the effects of Dact1 in brain development, using the mouse as a model system.

Mice genetically engineered to lack Dact1 will be used to examine the development of neurons and neuronal connections in the absence of this gene. The predoctoral fellow will test the hypothesis that loss of Dact1 causes a decreased number of synapses, or connections between neurons.

He will also investigate the consequences of the particular Dact1 mutation found in autistic patients on neuronal development and function. Determining how Dact1 affects neural development may provide an important clue towards understanding the biochemical processes involved in ASDs.

Christina Muratore
Northeastern University
$56,000 for 2 years

Influence of Oxidative Stress on Transcription and Alternative Splicing of Methionine Synthase in Autism

Many cases of autism are thought to develop due to environmental exposures acting on genetically vulnerable individuals. Potential environmental exposures encompass all non-genetic factors that might contribute to autism, including pesticides, manufacturing chemicals, heavy metals, and so on.

These toxins are thought to impair biochemical or metabolic processes which are critical for normal development and normal cognitive function. Most of these toxins are thought to cause oxidative stress and inflammation, and studies of autistic children have shown evidence of these processes in their blood and brains. In this study, the predoctoral fellow will investigate the link between oxidative stress and metabolism in a system related to neuronal function.

The vitamin B12-dependent enzyme methionine synthase is a metabolic protein that is extremely sensitive to environmental toxins, and levels of this enzyme have been found to be reduced in postmortem autistic brains. To determine whether the changes observed in brain samples can be detected non-invasively in patients, blood samples from autistic and control subjects will be analyzed for methionine synthase levels.

This could prove to be a valuable blood test in the diagnosis of autism. As well, biochemical and cellular experiments will be conducted to investigate the mechanisms by which oxidative stress affects the level and functional properties of methionine synthase.

This research may lead to a better understanding of the underlying mechanisms of environmental triggers in autism, as well as to a potential new tool for the diagnosis of autism. 

Elissa Robbins
Yale University
$56,000 for 2 years

Caspr2 Dysfunction in Autism Spectrum Disorders

The majority of cases of autism spectrum disorders (ASDs) are thought to arise from multiple “hits,” with many gene variants conferring a susceptibility to developing ASD. In rare cases, ASD appears to be linked to mutations in single genes which have particularly severe consequences for neural development.

Analysis of the functional properties of single-gene mutations leading to autism is critical for understanding the shared cellular and molecular pathways onto which ASD-linked mutations converge. Recently, novel mutations in the gene encoding the neuronal protein Caspr2 were identified in a large group of ASD patients. Caspr2 appears similar to several other proteins linked to ASD, which are located at the cell surface and are involved in the formation and maintenance of synapses, the sites of communication between neurons. The proposed research will investigate the role of Caspr2 in neurodevelopment, using the mouse as a model system.

Employing a variety of biochemical and cellular techniques, the predoctoral fellow will examine the effect of the ASD-linked mutations in Caspr2 on the development of the brain and its synapses. This study will further our understanding of how mutations in a single gene contribute to ASD, providing new insights into the causes of ASD and potential new therapeutic targets for the treatment of this disorder.

Aaron Shield
University of Texas, Austin
$56,000 for 2 years

Visual Perspective-Taking and the Acquisition of American Sign Language by Deaf Children with Autism

Although a great deal is known about how hearing autistic children acquire speech, very little is known about how deaf autistic children acquire American Sign Language (ASL). The visual nature of ASL may pose specific challenges to deaf autistic learners that are different from those facing hearing children in learning speech.

Children with autism have difficulty understanding other people’s thoughts and feelings, and an early step towards reaching this understanding is the recognition that other people’s visual perspectives differ from their own. Since sign languages are perceived visually, signers have to mentally take the visual perspective of their conversational partners in order to understand utterances properly. This research aims to study how deaf children on the autism spectrum acquire ASL.

The predoctoral fellow will examine the sign language of deaf autistic children in comparison with typically-developing deaf children. The children’s performance on a series of linguistic tasks will be analyzed in order to determine whether an impairment in visual perspective taking is evident in deaf autistic children, as well as what effect such an impairment may have on the acquisition of sign language.

Results from this study will give us a better understanding of visual perspective taking in sign language, which could help teachers of autistic children, both deaf and hearing, develop better instructional strategies for these children.

Amar Thyagarajan, Ph.D.
Massachusetts Institute of Technology
$95,000 for 2 years

Imaging synaptic neurexin-neuroligin complexes by proximity biotinylation: applications to the molecular pathogenesis of autism

A major underlying cause of autism is hypothesized to be defects in the development of synapses, which are the points of contact between brain cells through which brain cells communicate. During development, proteins located on the surfaces of contacting neurons physically interact to regulate the fate and function of the synapse. Two types of proteins, called neurexins and neuroligins, are examples of such synaptic proteins.

Mutations in genes encoding both of these proteins have been linked to autism, and it has been hypothesized that these mutations may impair the interaction between neuroligin and neurexin at the synapse. Dr. Thyagarajan will study the molecular properties of the neurexin-neuroligin complex in live neuronal synapses. They will use techniques from chemistry, neuroscience, and molecular biology to develop a novel technology to optically image the formation, dynamics, and function of protein complexes at live synapses.

They will use this technology to study neurexins and neuroligins during synapse development, and determine the effects of autism-linked mutations in these genes on the formation and functions of synapses. Insights from these studies may lead to a better understanding of the underlying biological causes of autism, and may aid in the future development of targeted therapeutic strategies.

Megan Williams, Ph.D.
University of California, San Diego
$110,000 for 2 years

The role of the autism-associated gene Tuberous Sclerosis Complex 2 (TSC2) in presynaptic development

Tuberous sclerosis complex is a genetic disorder caused by mutations in the gene TSC2. Many people who suffer from tuberous sclerosis complex also develop autism, but it is not understood how mutations in TSC2 cause autism.

Autism is thought to be caused at least in part by changes in the development and function of synapses, or the connections between neurons in the brain. During the first few years of life, the number of synapses between neurons increases dramatically, and over time these connections are edited so that any incorrect synapses are removed and only correctly made synapses remain. In this research project, the fellow will test the hypothesis that TSC2 is involved in this process of synaptic editing, and that loss of TSC2 causes neurons to have too many synapses.

To study the effects of the TSC2 gene product on synaptic editing, Dr. Williams will examine synaptic development in neurons from rats that have been genetically engineered to lack TSC2. She will determine whether the loss of TSC2 causes changes in the numbers of synapses made by these neurons. She will also examine the development of synapses in real time, to explore the possibility that TSC2 affects the dynamics of synapse formation and editing.

This study will help us further understand the function of the disease-causing gene TSC2 in neurons, and may point towards the development of new therapies in the treatment of autism and tuberous sclerosis complex.

Qiaojie Xiong, Ph.D.
Cold Spring Harbor Laboratory
$88,000 for 2 years

Neural circuit deficits in animal models of Rett Syndrome

Although autism spectrum disorder (ASD) is one of the most heritable cognitive disorders, the genetic causes of ASDs remain uncertain. It is thought that ASDs are caused by aberrant connections between neurons in the brain. It is not understood how multiple diverse genetic factors cause the common symptoms of ASDs but because many genes are involved in controlling the development of the neural circuits affected in ASDs, mutations in any of multiple genes could lead to the disruption of these circuits.

Thus, understanding how neural circuitries are altered in animal models of ASDs may provide insights into the etiology of this disorder. In the present study, Dr. Xiong will examine neural connectivity in a mouse model of autism. Using sophisticated imaging techniques, he will map short-range and long-range neural connections in the auditory cortex of mice lacking MeCP2, the gene mutated in Rett Syndrome, a genetic disorder which shares many common features with ASDs.

Determining which neural pathways, when disrupted, produce the autistic-like behaviors seen in the MeCP2 mutant mouse should provide insight into the neural pathways disrupted in autism. This study may provide insights into the neurobiology of autism, as well as help to develop a general and efficient strategy for relating genes to neurological dysfunction in rodent models of autism.

Jamil Zaki
Columbia University
$56,000 for 2 years

Informational and neural bases of empathic accuracy in Autism Spectrum Disorder

People with Autism Spectrum Disorder (ASD) have difficulties with communication and social interactions which likely stem from problems with social cognition, or the ability to understand the thoughts and emotions of others. While several tests have previously been developed to measure social cognition, these tests use relatively simple stimuli such as pictures or cartoons.

These stimuli are quite different from the emotions and thoughts people express in true social interactions, and thus it is unclear whether improved performance on these simplified tests of social cognition reflects real improvement the in social functioning of people with ASD. In the proposed project, the predoctoral fellow will use a more realistic Empathic Accuracy test to explore social cognition in ASD.

In the Empathic Accuracy test, participants attempt to identify the real emotions of people in videos, rather than still pictures or cartoons. This task requires the integration of verbal cues, non-verbal cues, and information about social situations in a flexible and dynamic way which more accurately simulates true social interaction. This test will be used to examine how people with ASD use different types of information in a social context to understand what other people are feeling, as well as to examine the neural pathways involved in understanding realistically portrayed emotions.

Using a more realistic measure of social cognition in the study of individuals with ASD may improve our understanding of the biological underpinnings of social difficulties in ASD, and may aid in the development of interventions to improve social functioning. 

Xuesong Zhao, Ph.D.
Dana-Farber Cancer Institute
$95,000 for 2 years

BDNF secretion and neural precursor migration

Autism is characterized by errors in the formation of connections between neurons. During brain development, neurons born in one area of the brain often must migrate to their final destination.

Because abnormal migration of neurons can cause abnormal connections to be formed between neurons, migration defects could be an underlying cause of autism. Genes that are involved in the control of migration are therefore potential candidates for involvement in autism.

One such gene is brain-derived neurotrophic factor (BDNF), which has been found to be expressed at increased levels in autistic patients. BDNF signals to migrating neurons to control the direction of their migration. In this study, Dr. Zhao and colleagues will study the role of BDNF in neuronal migration in further detail.

Using genetic and molecular techniques, researchers will identify the molecules that control how and where in the brain BDNF is produced and secreted. Various candidate genes and molecular pathways will be tested for their involvement in this process. Determining how BDNF expression and localization is regulated will provide insight into its effects on controlling neuronal migration.

This research will help to further define the genes and molecules involved in autism, and may provide new paths towards therapeutic approaches in the treating autism.

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