In the nine years that CAN has been awarding research grants, our program has expanded to accommodate the changing needs and visions of autism itself. The Pilot Project and Young Investigator grants selected this year include several areas of autism research that have, until now, been receiving much less attention than they deserve. These include immune and gastrointestinal function, environmental triggers and their interactions with genes, motor functioning, especially as a potential early predictor of autism, and brain physiology. The projects are meant to hit autism on all levels and move us from understanding autism on a descriptive level to understanding it on a biological level. Our one and only goal is for this knowledge to translate into opportunities for biologically relevant interventions and ultimately a cure for autism.
By seeding such projects and supporting those who want to make autism research their mission, parents, scientists and clinicians have come together to uniquely build the field of autism research. Although researchers play the major "hands on" role in making sure the science gets done, it would not happen without the constant involvement of the parent and donor community who choose to be active participants in this process. The Cure Autism Now Research Partner program is a means for donors to directly link themselves to specific scientists and sponsor their cutting-edge research. We are indebted to our 2006 Research Partners for their support of the Cure Autism Now mission.
Diagnosis/Assessment: Markers and tests to detect and evaluate autism symptoms earlier and more accurately
Autism-specific Impairments in the First Six Months of Infancy (Young Investigator Award)
Anjana Bhat, Ph.D., Kennedy Krieger Institute, Baltimore, MD
Impaired visual attention and affect may be early signs for autism and may impair infants' early learning abilities. Hence, the purpose of the proposed research is to conduct a prospective study to identify autism-specific impairments in visual attention, affect, and learning in infant siblings of children with autism at 3 and 6 months of age as compared to preterm and typically developing infants. Infants will be examined during a classic contingency learning paradigm known as the Mobile paradigm. The Mobile paradigm is an ideal form of assessment in multisystem disorders such as autism because it provides a multisystem assessment by taxing various developing systems such as the cognitive systems: arousal, motivation, and learning; sensory-perceptual systems: visual attention, proprioception; and motor systems: limb control and coordination. We hypothesize that infants later diagnosed with autism will specifically lack social attention and positive affect during the social interactions in the Mobile paradigm test, and that they will not display learning as compared to the typically developing infants. A better understanding of autism-specific impairments in the first six months of life will not only assist in early diagnosis but also provide a theoretical basis for developing effective early intervention programs.
Research Partner: The Karma Foundation
Gaze Patterns in Autism Across the First Two Years of Life (Pilot Project Award)
Sally J. Rogers, Ph.D., M.I.N.D. Institute, University of California, Davis
During the first two years, infants develop increasingly complex social and communicative abilities. Because autism is such a devastating disorder, and because young children with autism are quite responsive to early interventions, the hunt is on for early markers of incipient autism in infancy. Abnormal gaze patterns may be one such marker. This study will use new eye tracking methodology to record infant gaze behavior during live reciprocal social interaction, and when viewing recorded social stimuli. We hypothesize that gaze abnormalities will characterize autism from an early age. The project will identify differences in gaze behavior associated with autism at 12 and 24 months in a group of toddlers who are at high risk for autism (due to the presence of a sibling with autism in the family), compared to a control group. We will examine the consistency of gaze abnormalities across the first two years of life in these children using previously gathered longitudinal data.
Research Partner: The Mellanby Autism Foundation at The Giving Back Fund
Development of Motor Coordination and Anticipatory Control in Children with Autism (Pilot Project Award)
Deborah E. Thorpe, Ph.D., PT, PCS, University of North Carolina, Chapel Hill
Autism is characterized by deficits in sociability, communication and restricted behaviors. In addition to these core features, research suggests that movement abnormalities are evident in autism. Anecdotal reports often describe a variety of motor difficulties affecting functional skills such as writing, tying shoelaces, or playing sports. Although these types of difficulties may be related to dyscoordination and deficient anticipatory control mechanisms, there is a dearth of empirical research about the development of these movement abnormalities in children with autism, and how these motor patterns differ from peers. The proposed study will analyze the development of specific fine motor patterns in young children with autism disorder (2-6 years) using an experimental grasping task. We also aim to determine whether or not motor deficits (e.g., difficulty anticipating or coordinating the timing of movement) are specific to autism disorder, and how much they affect functional skills. These findings will assist in understanding the nature of autism, and have implications for earlier intervention during a period where motor skills are critical to success in educational and social situations.
The Identification of Non-Verbal Oral, Motor Speech and Phonological Impairment in Individuals with Autism Spectrum Disorder (Pilot Project Award)
Shelley L. Velleman, Ph.D., University of Massachusetts, Amherst
Half of all children with Autism Spectrum Disorders (ASD) do not communicate by speaking. The nature of their speech problems is not understood. There are three possible causes: muscle weakness (dysarthria), poor motor programming/planning (apraxia), or limited ability to represent words as sounds in their minds (phonology). In a preliminary study, it was found that 60% of children with ASD had at least some of these factors. The purpose of this project is to test children with ASD to determine exactly what their speech problems are. We aim to develop a diagnostic measure useful for the identification and differentiation of subgroups of children with speech impairments. This will allow proper treatments to be developed and help provide specialized training for future speech-language pathologists focused on assessment and treatment of speech disorders in children with ASD.
Immunological Phenotyping in Autism: A Screen for Potential Early Biomarkers of Activation (Pilot Project Award)
Paul Ashwood, Ph.D., M.I.N.D. Institute, University of California, Davis
It is thought that the interaction of genetic susceptibility and exposure to nongenetic influences during critical periods of neurodevelopment plays a part in the development of autism. Virtually the entire research literature on autism emphasizes the multiple facets of this disorder. Taken together, these data indicate that ASD is, in reality, a group of disorders that share a common behavioral profile. To make progress in identifying the causes of these disorders it will be essential to develop diagnostic markers that will lead to unequivocal differentiation of the various phenotypes. We aim to demonstrate the presence of distinct immune phenotypes in ASD based on the level of activation of their immune response. We will identify and characterize the immune response in ASD by comparing the activation status and function of lymphocyte cell populations and their cytokine/chemokine profiles, firstly in peripheral blood and secondly in isolated cell cultures that receive immunological challenge. Immunological findings will be correlated with behavioral and biomedical factors to examine the relationship between the immune responses and clinical characteristics of autism. By elucidating the medical and biological correlates of autism, we hope to contribute to a clearer understanding of the early biological processes underlying this increasingly common disorder. A better understanding of the underlying biology may contribute to earlier identification and the development of more individual-based treatment regimens.
Research Partner: Peter Emch
Microglial Regulation of Cholinergic Development in the Basal Forebrain (Pilot Project Award)
G. Miller Jonakait, Ph.D., New Jersey Institute of Technology
While the neurobiological basis for autism remains poorly understood, neuropathological studies have detected structural abnormalities in certain brain regions suggesting that disruption of normal brain development may play a role in the disorder. Our work highlights one of those abnormal brain regions, the so-called cholinergic basal forebrain, that innervates important brain areas serving cognitive function. Autistic children have too many neurons in this region, but how such changes might occur in development has not been explained. Increasing evidence also suggests that fetal exposure to infectious agents or toxins with associated inflammation may play a role in the development of autism. Such infection or toxicity can extend to the embryonic brain where local inflammation might prove detrimental to the developing brain. Our own work performed on cultured rodent cells suggests that abnormal embryonic brain inflammation during development leads directly to abnormal neurodevelopmental outcomes. Specifically, it leads to the excess production of cholinergic neurons in the basal forebrain. Thus, we have shown directly that brain inflammation has important neurodevelopmental consequences. Our proposal seeks to extend those studies by investigating in vivo whether maternal infection will lead to a similar excess of cholinergic neurons in the fetal brain. We will also seek to determine whether several known inflammatory signals will act similarly in culture and what developmental mechanisms they might use to create excess numbers of these neurons. Finally, we hope to begin to identify the specific molecules that cause the basal forebrain to develop abnormally.
Research Partner: The Gassin Family Foundation
Histologic, Microbiological and Molecular Analyses of Bowel Disease in ASDs (Pilot Project Award)
W. Ian Lipkin, M.D., Columbia University
Debilitating gastrointestinal (GI) dysfunction is described in some autistic children, possibly at higher frequency in individuals with a regressive phenotype. Its cause is unknown; however, some studies have implicated inflammation or infection. The significance of gastrointestinal dysfunction for brain dysfunction is controversial; some investigators have proposed that differences in GI microflora induce inflammation, influence permeability of the GI tract, or release novel neuroactive peptides that have remote effects in brain. Our project will use sensitive new assays for gene expression, microbiology and immunology to survey GI tract biopsies and blood from two groups of children: one group with GI dysfunction and autism, and one group with GI dysfunction but no neurological disturbance. The implication of an infectious agent (or agents) as factors (or cofactors) in autism or associated GI comorbidity could lead to new strategies for prophylaxis or therapeutic intervention. Discovery of distinct profiles of gene expression in GI tract or of soluble factors in peripheral blood may provide insights into pathogenesis; inform genetic analyses; and facilitate management by providing therapeutic targets and objective criteria for diagnosis and treatment response.
A Role for Immune Proteins in Early Stages of Neural Development: Possible Implications for the Pathogenesis of Autism (Pilot Project Award)
A. Kimberley McAllister, Ph.D., University of California, Davis
Proper formation of connections in the brain during childhood provides the substrate for adult perception, learning, memory, and cognition. Tragically, improper formation or function of these connections leads to many neurodevelopmental disorders, including autism. Autism spectrum disorder is a highly prevalent severe neurobehavioral syndrome with a heterogeneous phenotype. Although there is a strong genetic component to autism, the syndrome can also be caused or influenced by nongenetic factors. Specifically, maternal viral infection has been identified as the principle nongenetic cause of autism. Several studies have even indicated a genetic link between autism and immune system genes. Since immune molecules are increased following infection and are present in the developing brain, it is possible that changes in these immune molecules lead to changes in neuronal connectivity that underlie some forms of autism. This proposal will test this idea by studying the function of altered levels of a specific kind of immune molecule on the initial formation of connections and their subsequent plasticity in the developing brain. Thus, our results should reveal a mechanism for the primary nongenetic cause of autism and thereby illuminate potential preventive therapies for this devastating disease.
Research Partner: The Gassin Family Foundation
Polybrominated Diphenyl Ethers as a Potential Neurodevelopmental Toxicant (Pilot Project Award)
Irva Hertz-Picciotto, Ph.D., M.P.H., University of California, Davis
Both genetic and environmental factors contribute to autism in the majority of cases, yet few specific causes have been identified. In the search for relevant environmental exposures, chemicals affecting neurodevelopment are prime suspects. One such group of chemicals is the polybrominated diphenyl ether (PBDEs). These are flame-retardants used widely in consumer products, including plastic casings for television sets and computers, construction materials, carpeting and foam cushions. Levels of PBDEs are rapidly increasing in the environment and in human tissues, with body burdens in California among the highest worldwide. Of foremost concern is the neurodevelopmental toxicity of PBDEs demonstrated in animal studies. Prenatal exposures alter spontaneous behaviors, adversely affect learning and memory, and result in a lack of ability to habituate to a novel situation. PBDEs cross the placenta, accumulate in the fetus, and disrupt thyroid hormones, which are crucial for early brain, motor, language and sensory development. Thus, we will measure PBDEs in serum collected from children participating in a large epidemiologic study of autism. The CHARGE (Childhood Autism Risk from Genetics and the Environment) Study has enrolled over 400 subjects, including children with autism, children with developmental delay, and children from the general population. Over 300 of these children gave blood samples, from which we will select 90 (30 from each group) for measurement of PBDEs. This project will provide preliminary data to determine whether children with autism have higher concentrations of PBDEs than those from the general population or those with developmental delay but not autism.
Research Partner: Shirley Craven Foundation
Molecular and Environmental Influences on Autism Pathophysiology (Young Investigator Award)
Janel Le Belle, Ph.D., University of California, Los Angeles
The incidence of macrocephaly (enlarged head) in the population of autistic patients is considerably higher than in control populations and indicates that this may contribute to the development of ASD. We are interested in what genetic and environmental changes underlie the development of macrocephaly and autism. Mutations in PTEN can be found in some autistic patients with macrocephaly. We have a mouse model of macrocephaly in which the gene PTEN has been deleted, resulting in the abnormal growth of brain cells, producing animals with large heads. We have recently shown that PTEN has a role in the ability of normal brain stem cells to self-renew, proliferate, and grow. We will use a relatively new technology in the study of gene expression in the brain, called microarray, to identify genes that are changed in our macrocephalic PTEN mutant mice. These experiments may identify genes and gene networks that contribute to ASD. We will also study how PTEN activity is affected by environmental factors. One such factor is oxidative stress. Oxidative stress is a general term used to describe oxidative damage to a cell, tissue, or organ, caused by reactive oxygen species. Most reactive oxygen species come from the internal sources as byproducts of normal cellular metabolism, such as energy generation from mitochondria. External sources include exposure to cigarette smoke, environmental pollutants such as emission from automobiles and industries, consumption of alcohol in excess, asbestos, exposure to ionizing radiation, and bacterial, fungal or viral infections. We and others have found that low levels of oxidative stress can enhance the self-renewal and proliferation of brain stem cells when grown in a culture dish, and this also results in decreased amounts of PTEN gene expression. We propose to look further at this potential mechanism by over-expressing pro-oxidant genes and disrupting anti-oxidant genes in cultured cells and in developing mouse embryos to determine if oxidative stress is a key environmental factor in the development of ASD with macrocephaly.
The Jonathan Pettigrew Memorial Award
Genetic Susceptibility to Mercury-induced Immune Dysfunction in Autism and Autism- Spectrum Disorders (Pilot Project Award)
Ellen K. Silbergeld, Ph.D., Johns Hopkins Bloomberg School of Public Health
The goal of this project is to examine genes that may affect responses to environmental risk factors in autism and autism spectrum disorders (ASD). These are complex diseases that are known to involve interactions between genetic susceptibility and acquired (or environmental) exposures. However, most research on autism/ASD development has not examined these interactions, but rather focused on either genetic or environmental risk factors, including mercury compounds. The failure to include gene-environment interactions may be one reason why we have not yet identified either key genes or significant environmental risk factors associated with autism/ASD. We plan to examine whether there are differences in how children with autism/ASD respond to one environmental contaminant (mercury) compared to their unaffected siblings and parents. We hypothesize that mercury does not cause autism by itself, but that individuals who carry certain variations in specific genes may have heightened responses to mercury, and that these variations will increase the likelihood that those children exposed to mercury will develop autism/ASD. In order to accomplish our goal, we will first develop and validate a panel of tests using immune cells found in human blood to quantitate immune responses to mercury in vitro by using the blood of healthy volunteers. Then we will apply this panel to cells obtained from children diagnosed with autism/ASD, their unaffected siblings, their parents, and unrelated community controls. This project will be the first study on this topic conducted in cells from human subjects. Eventually, we hope to identify variations in specific genes related to these responses to mercury for use in epidemiological studies of autism/ASD.
Research Partner: Robert and Joni Bell
John J. Foxe, Ph.D., City College of the City University of New York
It has long been speculated that children and adults with autism have difficulties in dealing with or combining information across the senses. This has become known as sensory integration theory and the predictions of this theory are far-reaching. If sensory integration is a core deficit, then a number of additional attributes of autism might very well be explained by this problem. For instance, our research has shown that normal integration of auditory (heard) and visual (seen) information is absolutely critical for speech recognition, particularly in busy or noisy environments. Clearly, this could also lead to real difficulties in the ability to recognize emotion and social cues in speech. Remarkably, despite the prominence of this theory, little direct investigation of multisensory processing has actually been conducted in autistic individuals. Work by this team has detailed a series of multisensory brain processes through electrophysiological measures and using functional imaging. Here, we propose to measure these previously established effects in autistic children. Specifically, we will 1) assess basic auditory-visual integration during a very simple detection task, 2) assess auditory-visual integration during a slightly higher-level identification task where subjects are asked to identify simple animal pictures and sounds and lastly 3) we will assess whether autistic individuals use multisensory visual information effectively when interpreting speech in noisy environments. By relating results across these three levels of investigation, we will be able to assess for the first time whether basic deficits in multisensory processing really do exist in this population and whether such deficits might be one of the root causes of higher-level deficits such as inability to recognize speech in distracting environments. We believe that it is imperative that a methodical scientific approach be finally taken to assess the well-known sensory integration theory of autism.
The Frank del Olmo Memorial Award
Electrophysiological Indicators of Gating and Timing Abnormalities in Autism (Pilot Project Award)
Katherine M. Martien, M.D., Massachusetts General Hospital
Individuals with autism can have inaccurate processing of sensory information from both external environment (i.e. auditory, visual, tactile, and taste) and internal milieu (i.e. pain, proprioception and vestibular). This produces a cumulative effect on the developing brain that further undermines the way the brain matures and functions. Some researchers have proposed that the autistic brain has two particular basic abnormalities: 1) gating problems - that is, difficulty regulating how intensely the brain responds to sensory stimulation, and 2) timing problems - that is, a tendency for communication among parts of the brain to be poorly synchronized with each other. The processing and integration of sensory information in the brain can be studied at the biological level using electrophysiological techniques that measure the quality of the transduction (transformation) of environmental information into neuronal activity in the brain. In the present study we will examine the processing of auditory and visual information young autistic children using ERP and qEEG in an effort to identify the abnormalities in early and later signal processing, the relationship between early and late abnormalities, and how these signaling derangements contribute to abnormal patterns (and probably reduction) of coherence (synchronization) of brain functioning at the highest levels of information processing. We hope through our inquiries to find a level at which we can describe common features that are distinctive to autism, and also to identify subgroups with distinctive brain patterns that may also have distinctive underlying biological contributing factors. This will be helpful at many levels of autism research, diagnosis and treatment.
Research Partner: The Gassin Family Foundation
Integration of Faces and Vocalizations in the Primate Prefrontal Cortex (Pilot Project Award)
Lizabeth M. Romanski, Ph.D., and Tadashi Sugihara, Ph.D., University of Rochester
The integration of faces and voices is crucial for recognizing and remembering objects, and for communicating effectively. Some have theorized that it is this inability to synthesize information, especially during communication, which lies at the heart of autism. Although many brain regions are involved in integrating communication information, we believe that the frontal lobes are essential and may be one of the brain regions critically affected in autism. In this project, we will examine how single cells in the frontal lobes integrate face and voice information using an animal model. Specifically, we will record the neurophysiological responses of auditory and visual neurons in the frontal lobe of awake macaque monkeys who will be presented with vocalizations and corresponding facial gestures. Our preliminary data indicate that some frontal lobe neurons show an enhanced response to simultaneous presentation of matching faces and vocalizations especially when presented in naturalistic "movie" format. It is our hope that these studies will: lead to additional diagnostic tests perhaps based on our naturalistic face-vocalization paradigm, behavioral therapeutic interventions aimed at training appropriate face and vocalization matches, and treatments aimed at repairing impaired cellular mechanisms of sensory integration which may have been altered in autism.
Brain Dynamics of Multisensory Integration in Autism Spectrum Disorders (Pilot Project Award)
Clifford D. Saron, Ph.D., and Susan M. Rivera, Ph.D., University of California, Davis
Multisensory integration (MSI), the combination of various senses to form a single integrated experience of the world, is essential to everyday life. Current research shows that there are both co-operative functions of the senses as well as inhibitory effects of one sensory system upon another that contribute to our ability to form this integrated experience. Many researchers have suggested that the formation of cross-sensory associations may be deficient in children with autism. Indeed, the well-known author with autism, Temple Grandin, has repeatedly discussed sensory integration difficulties as being at the core of her autism. The current project will examine the behavioral (reaction time), electromyographic (EMG), and brain (EEG) responses to sensory processing in children with Autism Spectrum Disorders (ASD) as compared to typically developing (TD) children. Specifically, we will examine the integration of multiple sensory systems through analysis of dense-channel array event related potentials (ERPs) elicited in response to visual, auditory, and somatosensory stimuli delivered alone or in simultaneous combination. We will investigate the brain regions involved in MSI, and probable differences in their function in autism. We predict that, compared with TD children, ASD individuals will show less improvement in a reaction time test and generally smaller electrocortical activations related to MSI when multiple sensory systems are engaged.
Cellular and Molecular Deficits: Pinpointing underlying defects and their mechanisms
Alterations in Specific Subtypes of Glutamate Receptors in Autism: An Autoradiographic and Molecular Study in the Cerebella Cortex (Pilot Project Award)
Gene Blatt, Ph.D., Boston University School of Medicine
The etiology of autism has remained elusive despite an increase incidence of the disorder. Treatment has largely targeted behavioral symptoms instead of the underlying substrates which remain unknown. The present research proposal investigates a neurotransmitter system, the glutamate system, which provides excitatory input to key nerve cells throughout the brain. One area of the brain, the cerebellum has received much attention because a cell type critical to its function is decreased in number. Once considered to only modulate motor function, there is now compelling clinical and neuroanatomical evidence that the cerebellum also modulates cortical structures involved in higher thought processes. The glutamatergic systems in the cerebellum provide a delicate excitatory-inhibitory balance so that the output of the cerebellum functions properly. Identification of which specific glutamatergic receptors and receptor subunits are altered in the cerebellum in autism can lead to therapeutic intervention targeted to the defective receptors instead of just treating behavioral symptoms. It will also give valuable leads to geneticists who can locate defective candidate gene(s) to determine whether there is a high incidence in the families of autism children which can ultimately lead to screening high-risk families for the disorder.
Research Partner: The Gassin Family Foundation
The Role of Neuroligin in Synaptic Remodeling of Neuronal Networks (Pilot Project Award)
Michael A. Colicos, Ph.D., University of Calgary, Canada
Synaptic remodeling is believed to be a fundamental mechanism of learning and memory, and the resulting connections that are made between neurons are thought to be the basis for cognition. Disorders in this process are hypothesized to contribute to cognitive dysfunction, such as observed in autism spectrum disorder (ASD). We plan to study the process of synaptic remodeling and to characterize a protein, neuroligin, which is both associated with remodeling, and found to be mutated in some autistic patients. We need to understand how the autism associated mutation affects the connectivity between neurons, as it is this connectivity that defines our cognitive function. To do so, we have developed a unique technology, non-invasive photoconductive stimulation, which allows us to visualize the entire process of synaptic remodeling in cultured mammalian neurons grown on silicon wafers. This technique also allows for the expression or functional inhibition of specific molecules in the neurons, which will allow us to determine their role in the reorganization process. Neuroligin is a synaptic cell adhesion molecule that is involved in both synaptogenesis and in regulating synaptic transmission through the N-methyl D-aspartate (NMDA) receptor. We wish to understand the role of neuroligin and NMDA currents in the process of synaptic reorganization. By learning the functional consequences of the ASD mutation on synaptic transmission and plasticity, we hope to understand how such cognitive dysfunctions occur, and then be able to directly test in vitro therapeutic strategies using the same technology.
Self-Injurious Behavior: Pharmacological Studies in a Rat Model (Pilot Project Award)
Darragh P. Devine, Ph.D., University of Florida
Self-injurious behavior is seen in a substantial number of autistic children. The behavior disorder is determined at least partly by abnormal brain chemistry, but the brain functions that contribute to self-injury are not very well understood. The severity of self-injury ranges from mild to very severe, and these behaviors constitute an extremely debilitating symptom of autism. They are also extremely destructive for families who live with self-injurers. Many autistic self-injurers respond well to behavior therapy, and this is clearly the treatment of choice. However, there is no drug that works for all self-injurers, and research to seek out and test new drugs is not well developed. We are working with a pemoline-induced model of self-injury in rats, to evaluate drugs that may be useful in clinical treatments for self-injury. We do not allow the rats to do any serious self-harm but are testing specific drugs to see if they will prevent the rats from starting to bite at themselves. We plan to work with drugs that have been used in autistic self-injurers to further evaluate the efficiency of the model to identify effective drug therapies, and we will begin to test a new drug that we think may have beneficial effects. At the same time, we will examine the brains of the rats to identify differences in brain chemistry between the rats that self-injure, and those that do not when they are treated with pemoline or the drugs that block the self-injurious effects of pemoline. These studies will help us to understand the biological basis of self-injurious behavior, so that we can better develop effective treatment strategies. These studies may also provide a mechanism to pre-screen potentially promising drugs before they go to clinical trials and reduce the risk that ineffective drugs would be tested in autistic self-injurers.
The Relationship between Autism and Cholesterol Metabolism (Pilot Project Award)
Robert D. Steiner, M.D., Oregon Health and Science University
Cholesterol production is necessary for normal cell development and functioning. Smith-Lemli-Opitz syndrome (SLOS) is a genetic metabolic condition caused by a defect in cholesterol production by the body, with physical and mental difficulties. Most people with SLOS have autistic behaviors. Because SLOS is caused by a problem with cholesterol production, we think cholesterol production may have a role in causing autism in people who do not have this genetic condition, but just have autism. Our plan is to evaluate cholesterol metabolism in people who have autism and people who do not have autism to determine if there are differences. We will look at whether there is a relationship between cholesterol production and the severity of autistic behavior. We will also see if individuals with autism are more likely to have SLOS gene mutations than those who are not autistic, and whether family members of SLOS patients (who carry the SLOS gene) have features of autism. This will involve enrolling 45 children with autism (who do not have SLOS) from our autism clinic, 45 non-autistic, non-SLOS children, and 20 SLOS carriers. The children will have blood samples taken for analysis of cholesterol metabolism. Our findings will determine if indeed cholesterol production plays a role in causing autism. If it does, this will have implications for screening, diagnosis and treatment of autism.
Genetic and Neurobiological Analysis of Sociability, an Autism Endophenotype, in a Mouse Model System (Pilot Project Award)
Edward S. Brodkin, M.D., University of Pennsylvania School of Medicine
Impairments in social interactions are among the most prominent, disabling, and treatment-resistant symptoms of autism. A major goal of autism research is to identify genes relevant to sociability (defined as a tendency to seek social interaction), and to elucidate the function of those genes in brain development and behavior, which ultimately should advance our understanding of and ability to treat autism. To accomplish these goals, it will be crucial to develop a mouse model of sociability. We have recently initiated genetic studies of sociability in mice, and have identified genetically influenced differences among inbred mouse strains in sociability. The aims of the current proposal are 1) to further develop this mouse model system for autism research; 2) to assess the effects of particular autism candidate genes on sociability in this model system by measuring the sociability of mice in which those genes have been deleted (gene "knockout" mice); and 3) to identify brain regions that are involved in sociability, and to study differences in gene expression in such a brain region in mice that differ greatly in sociability, using GeneChip technology. These proposed studies can help to elucidate the genetic and neurobiological basis of highly disabling symptoms of autism.
Identification of Candidate Genes for Autism Spectrum Disorders (Young Investigator Award)
Yuhei Nishimura, Ph.D., University of California, Los Angeles
Autism is a heterogeneous condition and is likely to result from the combined effects of multiple, subtle genetic changes interacting with environmental factors. We hypothesize that there are genes whose expression are deregulated in autism. We believe that a subset of these genes can be identified through whole genome expression profiling in lymphoblastoid (white blood) cells from individuals with autism and matched controls (the AGRE collection). Although lymphoblastoid cells are not neuronal cells, recent studies suggest that lymphoblastoid cells can be useful to detect biologically plausible correlations between candidate genes and disease in various neuropsychiatric disorders. Our preliminary study using lymphoblastoid cells from autistic subjects with known genetic disorders also suggests that an approach based on lymphoblast gene expression profiling could be widely used to subgroup subjects with idiopathic autism and to identify candidate genes for autism. The ultimate goal of the proposal is to identify a set of genes that are deregulated in autism and then test these candidate genes for autism on a broader cohort of children with autism and in analysis using human brain tissue.
Research Partner: The Gassin Family Foundation
A Proteomics Approach to the Identification and Characterization of Protein Targets Regulated by UBE3A (Pilot Project Award)
Lawrence T. Reiter, Ph.D., University of Tennessee Medical School
The purpose of this grant is to focus on the detection of genes involved in autism. UBE3A mutations cause a mental retardation disorder known as Angelman syndrome and duplication of this gene has been implicated in as many as 2% of all cases of inherited autism. This project will take advantage of the genetic power of Drosophila melanogaster (fruit fly) as a model system to identify genes regulated at the protein level by UBE3A. In the project we propose several techniques that allow us to generate artificially high levels of normal and mutant fly dube3a proteins in flies. We will then use protein sequencing (proteomics) to identify those genes affected by changes in the level of fly dube3a protein. Genes that appear to change in this analysis will be subjected to validation using physical association studies in cell culture and a previously published mouse model of Angelman syndrome that is lacking mouse Ube3a protein. Finally, we will screen the AGRE collection to determine if any of the genes we identify are involved in genetic risk for autism. These targets may prove useful in the future as therapeutic targets for the treatment of disorders like Angelman syndrome and autism.