Young Investigator and Pilot Project grants for the upcoming year. In 2006, our tenth year of offering these awards, Cure Autism Now received a record number of grant requests. Looking at our grant program overall, the number of applications has quadrupled in a mere two years, providing a stunning index of the intensity of the increased focus on autism within the research community.
The Pilot Project and Young Investigator grants were conceived of as a mechanism to support novel research of the highest scientific quality. These projects may still be at a beginning stage or too speculative -- too “outside the box” -- to be supported by traditional means. Because of the complex nature of autism we never know from where the critical breakthroughs will come, and the awards were intended to pursue all avenues of autism research. Indeed, the 2007 grants attack the problem of autism on all biological fronts – from investigating immune, metabolic and gastrointestinal function; to researching environmental triggers; to tracing brain connectivity; to hunting down events that occur during the very first year of life in order to provide even earlier detection. These grants were also designed to serve as an impetus for more bright minds to enter the autism field. Besides the four Young Investigator grants awarded this year, this group of grants includes nine investigators who are new to the field of autism research. Collectively all these researchers are bringing their wisdom and perspective to bear on autism, and we are grateful.
As researchers find government money generally harder to secure, and redoubled autism awareness efforts bring the cause to the mainstream, the commitment of generous supporters to Cure Autism Now funded research and treatment efforts becomes more central to keeping progress racing forward. If you wish to become a part of the Hope for Our Children Campaign to significantly accelerating funding for autism research, please contact Bret Prichard, Vice President of Development, for more information.
Environment:The impact of our surroundings upon developing autism
Risk for Developing Autism: A Population-Based Longitudinal Study of Obstetric and Neonatal Factors (Pilot Project Grant)
Linda Dodds, Ph.D., Dalhousie University, Canada
Autism is part of a spectrum of disorders that are characterized by severe impairment in social interaction and communication and by the presence of inflexible behavior. Numerous reports suggest a trend of increasing rates of autism in Canada and in other countries, although it is not clear whether this increase reflects increased awareness of autism and changes in the way autism is diagnosed or whether the increase reflects true population increases in the disorder. Little is known about the causes of this disorder. Several recent studies have suggested that problems in pregnancy or in the newborn period may play a role in the development of autism. The purpose of this study is to use a population-based approach to identify pregnancy and newborn factors that are associated with the subsequent development of autism. Understanding the role of early life factors that are related to the development of autism is a first step towards early diagnosis and intervention.
Impact of Maternal Infection on Neurodevelopment – Structural and Functional Changes (Pilot Project Grant)
Geoffrey B.C. Hall, Ph.D., McMaster University, Canada
Although autism has a strong genetic component, early exposure to environmental insult may be a significant risk factor for the disorder. Exposure to known viruses during the first trimester of pregnancy has been connected to higher rates of autism. Animal modeling can be used to directly test if early exposure to immune challenges causes changes in brain structure, function and behavior that resemble changes seen in individuals with autism. Dr. Hall is interested in studying the behavior of mice that have been exposed to viral infection in-utero. Importantly, he will be assessing the neurological origins of these behaviors. Using recently available animal imaging methods he plans to assess the outcomes of maternal infection upon brain pathways key to autism, focusing especially on the dopamine and serotonin neurotransmitter systems. These methods offer the advantage over other techniques that the same animal can be studied across time. This provides the exciting opportunity to also study the effects of environmental manipulations on behavioral outcomes, and connect these results to the neurological changes seen throughout development. The overall objective of this study is to localize and quantify molecular events that occur in offspring as a result of maternal infection. This work holds promise for the development of new diagnostic tools and improvements in intervention.
Cellular, Physiological and Molecular Mechanisms Underlying Alterations in CNS Development Caused by Exposure to Clinically-Relevant Levels of Mercury-Containing Compounds (Pilot Project Grant)
Mark Noble, Ph.D., University of Rochester Medical Center
Dr. Noble's research aims to understand the mechanisms by which genetic factors and environmental insults combine to disrupt normal brain development and cause complex neurological syndromes such as autism spectrum disorders (ASD). His laboratory is interested in understanding how identical insults can have different outcomes in different individuals. The goal of the research is to provide a mechanistic understanding of vulnerability to physiological stressors implicated in ASD. Previous work from the Noble lab has shown that the state of oxidative stress of individual cells (“redox state”) controls how they react to various environmental agents. The importance of redox states in controlling multiple cell functions is of potential interest given the observations that some data suggests individuals with ASD show signs of being in a more oxidized status. This condition may make them more vulnerable to physiological stressors. These studies will focus on thimerosal and methyl mercury in order to understand the cellular basis for vulnerability to these toxicants, and are designed to provide general principles relevant to understanding how any toxicant impinges on normal cell development. As a part of the proposed research, Dr. Noble aims to uncover approaches to identifying oxidative stress that could provide the basis for early identification of children at particular risk of damage from environmental toxins. They will further apply this knowledge to the identification of a means to protect such individuals by studying the efficacy of anti-oxidant compounds in protecting against the cellular effects of thimerosal and methyl mercury.
Diagnosis/Assessment: Markers and tests to detect and evaluate autism earlier and more accurately
An Examination of Ocular Motor Functioning in Young People with Autism: Furthering Current Neurobehavioural and Clinical Definitions (Young Investigator Grant)
Joanne Fielding, Ph.D., Monash University, Australia
Current methods of diagnosis of autism spectrum disorders rely predominantly on subjective behavioral and clinical assessments, making it unclear whether the spectrum comprises distinct disorders or variants of the same disorder. Objective criteria with which to distinguish subgroups of individuals is crucial for the development of interventions that may more effectively treat, or even prevent, these disorders. Assessment of motor functioning is an area of research which has shown considerable promise in revealing qualitative differences. Yet, to date, the clinical significance of motor dysfunction has been often overlooked. The finding that abnormal movements appear before social and linguistic difficulties suggests that motor dysfunction may actually underlie some of the core characteristics of autism spectrum disorders. Eye movements offer a sensitive and accurate measure of motor dysfunction. This project aims to improve the diagnosis of children with autism, by comprehensively profiling, comparing and contrasting eye movement control in children on the spectrum. The neural mechanisms controlling eye movements are well-defined, permitting insights into patterns of abnormality that can provide important clues about location of neuropathology. These results will enhance current clinical descriptions of motor dysfunction in autism spectrum disorders, and help clarify whether their neurobiological underpinnings are differentially disrupted.
A Pilot MRI Study of Infants at High Risk for Autism (Pilot Project Grant)
Heather Cody Hazlett, Ph.D., University of North Carolina, Chapel Hill
New clues about the underlying neurobiology of autism have recently been reported from neuroimaging studies. In work conducted by Dr. Hazlett and colleagues, the brains of two year old children with autism were found to be significantly larger than that of their peers. Head circumference data from this same study showed that while children with autism have normal head circumference at birth, the trajectory for greater head size in autism begins to emerge around 12 months of age. This points to the period between 12 and 24 months as being of critical importance to understanding the development of autism. New methods in early detection and image processing developed by these investigators have now made it possible to examine early brain development during the first year of life. Therefore, in this new project, infants will receive brain MRI scans at 12 months and again at 24 months to explore the question of whether early brain differences can be detected in children at high risk for autism (identified by having an older sibling with autism). As the first longitudinal study of very early brain development, this project has the potential to provide important clues relevant to early detection and the early mechanisms underlying changes in the brain in autism. Co-Sponsor: The Gassin Family Foundation
Studying the Biology and Behavior of Autism at 1-Year: The Well-Baby Check-Up Approach (Pilot Project Grant)
Karen Pierce, Ph.D., University of California, San Diego
Although clinically undetectable, there is compelling evidence in some cases that something may be going wrong within the autistic brain from the first months of life. Research designed to reveal the causes of autism and to develop effective early treatments must begin during the infancy period. Unfortunately, both treatment and research on autism are necessarily linked to the age at which a confident diagnosis can be made. Current statistics confirm that the mean age of diagnosis in the US is not until a child is at least 3 years old, and in many places in the world, not until much later. Pediatricians who are in frequent contact with infants and their families are ideally poised to join efforts with scientists to study autism during the first year of life. Dr. Pierce's research project will investigate a pediatrician screening called the 1-Year Well-Baby Check-Up Approach that uses a previously validated screening tool (the CSBS-DP) as a method to refer for further evaluation infants who are showing signs of delay. They will follow the children through their 3rd birthday and anticipate that half of those infants who failed the screening form at the 1-Year Well-Baby Check-Up will go on to receive a final diagnosis of an autism spectrum disorder and the other half a developmental delay. If their identification procedure is successful, it could provide a model for a way scientists will be able to study autism within the first year of life, support the discovery of important biomarkers for infants at risk for autism, and allow treatment interventions to begin as early as possible. Co-Sponsor: Christopher and Jill Escher
Metabolic/Immune/Gastrointestinal: Searching for evidence to explain the broader symptoms
Oxidative Phosphorylation in Cells from Autistic Individuals Compared to Non-Autistic Siblings (Pilot Project Grant)
David Holtzman, M.D., Ph.D., Massachusetts General Hospital
Dr. Holtzman is interested in studying whether metabolic abnormalities contribute directly to the pathogenesis of autism. In preliminary studies, his lab has shown that cultured white blood cells from autistic patients have higher rates of using oxygen than do cells from their normal siblings. This finding suggests that higher rates in the autistic cells may allow the cells to adapt to an abnormality in the rate at which these cells make ATP, which is the critical form of energy in all cells in the body. In these experiments, Dr. Holtzman will use the cultured white blood cells to study the chemical steps which convert oxygen and glucose to ATP. His lab will also measure levels of ATP, mitochondrial number, and mitochondrial oxidative phosphorylation. These studies are designed to identify and determine the site of abnormalities in this critical set of chemical reactions in autistic patients, which possibly are central in the development of this disorder. If successful, these results will lead directly to studies of the genetic mutations or toxic reactions important in the development of autism. These studies of cell energy metabolism may also be developed as an additional diagnostic approach to this complex disorder.
The Overlap Between Celiac Disease and Autism - Potential Inflammatory Responses Exacerabated by Exposure to Toxicants Such as Mercury? (Pilot Project Grant)
Allen J. Rosenspire, Ph.D., Wayne State University
The aim of this grant is to research the connection between autism and celiac disease (CD). Celiac disease (CD), a digestive disorder that is characterized by intolerance to dietary gluten, is primarily recognized as an autoimmune disease of the small intestine. There is some evidence that individuals suffering from a variety of neurological disorders, including autism, often also suffer from CD, although the link needs to be better established. It is now clear that a particular antibody, anti-transglutaminase2 (anti-TG2), is strongly associated with having CD. A systematic survey for anti-TG2 in the blood of autistic children and their families has not yet been done. Therefore, Dr. Rosenspire will now test for anti-TG2 antibodies in serum samples archived in the Cure Autism Now AGRE repository. His hypothesis is that children with autism will have higher anti-TG2 titers than the general population, as well as their non-autistic siblings and parents. Knowledge of whether or not autism and CD are linked will advance our understanding of autism and disorders of the gut. Moreover, although CD clearly has a genetic basis, exactly how celiac disease could be connected to neurological disorders has been a mystery. Establishing an unambiguous link to autism will allow Dr. Rosenspire to pursue his hypothesis that CD may lead to inappropriate inflammation in the brain, and that patients with CD may therefore also be especially prone to adverse inflammatory responses upon exposure to environmental toxicants such as mercury.
Information Processing/Cognitive Abilities: Understanding how the complex behaviors of autism arise
Enhancing Mirror Neuron System Activity in Children with Autism Spectrum Disorders (Pilot Project Grant)
Mirella Dapretto, Ph.D., University of California, Los Angeles
Mirror neurons are a particular type of brain cells that have the unique property of firing both when an individual performs a goal-directed action, as well as when he/she observes the same action being performed by others. By directly translating an observed action into an internal representation, this mirroring system is thought to provide a mechanism by which others' actions, intentions, and emotions can be readily understood. Recent findings from several independent laboratories indicate abnormal functioning of this system in autism, which may account for many of the symptoms that characterize this disorder, particularly in the social domain. Previously Dr. Dapretto's group found that high-functioning children with autism failed to show significant mirror neuron system activity when observing and imitating emotional expressions. In the present study they will build upon other findings showing that activity in key brain regions can be increased by instructing children with autism to pay attention to important social cues. Specifically, Dr. Dapretto's lab will now address the fundamental question of whether they can significantly boost activity in the mirror neuron system in children with autism by explicitly directing their attention to relevant features of the stimuli/task. These studies have important implications for the potential ability to manipulate mirror neuron function in individuals with autism and, ultimately, whether strengthening the mirror neuron system may lead to behavioral improvements. Co-Sponsor: Harry G. DeMeo, M.D. – for Zackary DeMeo
Richard J. Krauzlis, Ph.D., Salk Institute for Biological Studies
Attentional issues are likely to contribute to many of the difficulties that people with autism experience in their everyday lives. Recent research shows that people with autism exhibit unusual performance in tasks that require them to discriminate visual stimuli or to search for particular objects amidst irrelevant items. These results suggest that basic elements of sensory-motor visual processing are fundamentally different in autism. The goal of this research is to identify which particular aspects of processing are affected, and how. One possibility is that the altered performance in autism is due to differences in how individuals with autism detect stimuli in their surroundings. Another possibility is that these alterations are due to how individuals with autism allocate attention to the different stimuli. A third possibility is that they are due to abnormalities in how individuals with autism evaluate the visual information and make decisions about what they see. Dr. Krauzlis will test these alternatives using video-game-like tests that allow him to separately quantify the effects of sensory processing, attention, and decision-making. The studies will provide information about fundamental issues that affect how an individual with autism interacts with the world. As it is already known that there is natural plasticity in the visuomotor pathways, investigating the mechanisms of attentional deficit may lead to the development of tasks that improve the deficit with training. Finally, an understanding of the basis of attentional dysfunction will also offer specific avenues for early diagnosis.
Neural Basis of Social Motivation Deficits in Autism (Young Investigator Grant)
Karli K. Watson, Ph.D., Duke University
One of the most debilitating symptoms of autism is a profound deficit in social behavior. Yet, despite the increasing prevalence of autism within the US population and the huge financial toll on society, the neural mechanisms underlying both normal and abnormal social behavior surprisingly remain very poorly understood. One reason for this lack of progress is the absence of a good model for studying the brain systems underlying human social behavior. Dr. Watson and her colleagues have developed an animal model suitable for neurobiological study that displays visually-guided social behaviors, which are present in typically developing human adults but disrupted in autism. Dr. Watson will probe the brain mechanisms supporting social behavior by specifically studying the activity of neurons in monkey orbito-frontal cortex (OFC), believed to be important in social function, while the animal engages in a social orienting task. Furthermore, neurochemicals such as oxytocin and serotonin have been shown to significantly alter social behavior in human and non-human animals. There is evidence that these systems are perturbed in autism. Therefore, Dr. Watson will determine how the manipulation of oxytocin and serotonin affects social motivation and OFC function in monkeys. This knowledge will give us a fundamental understanding of how social decision-making is accomplished in the brain, the first key step in identifying how the brain circuits of autistic individuals differ from those of typically-developing individuals. Identification of molecular systems responsible for social functioning could lead to the development of drugs designed to alleviate social pathologies found in autism. Co-Sponsor: The Gassin Family Foundation
Brain connectivity: Studying the anatomical and physiological networks that transmit information in the brain
Electrophysiological and Behavioral Investigations of Social-Emotional Integration in Young Children with Autism (Young Investigator Grant)
Joseph P. McCleery, Ph.D., Children's Hospital, Harvard Medical School Previous research suggests that children and adults with autism do not automatically process emotional expressions the way other people do, and that their brain activity during the processing of faces posed in emotional expressions is related to the severity of their impairments in social and emotional behavior. However, it is not currently known how differences in brain activity to emotional faces might cause difficulties with social and emotional behavior. The current study will test the hypothesis that children with autism process emotional faces and emotional voices in different areas of the brain than typically developing children. If this is true, it may help explain why children with autism pay less attention to other people's emotional expressions and have difficulty understanding them. Dr. McCleery will also study the children's responses to the emotional expressions of others in order to better understand how measures of brain activity during social information processing relate to social and emotional behavior. Together, these data will help to bridge the gap between known low-level sensory-perceptual abnormalities and deficits in diagnostic social-emotional behaviors in autism.This research will help us better understand the brain basis of impaired social and emotional behavior in autism.
Functional Cortical Connectivity in Autism (Young Investigator Grant)
Michael Murias, Ph.D., University of Washington Autism Center
This proposal investigates functional brain connectivity in autism spectrum disorder (ASD), measured via electroencephalographic (EEG) coherence. Current models of ASD postulate defects in integrative brain function. Large-scale brain abnormalities in ASD include early increases in brain growth and increases in grey and white matter volume. This suggests that altered connectivity among brain networks, rather than changes in function in any one brain region, may form the anatomical basis of cognitive impairments. EEG coherence quantifies the degree of synchronization between neural populations distributed across different parts of the brain. Coherence measures are believed to reflect the functional connections between brain regions, both in resting states and within the context of cognitive task demands. For example, by studying synchronous EEG oscillations, Dr. Murias found that in adults with autism the frontal lobe appears poorly connected with the rest of the brain. The goals of the current project are to develop methods of coherence analysis suitable for children, to compare resting state coherences between ASD and matched control children, and to develop experiments in which functional connections are measured under naturalistic social situations. Given the hypothesis that ASD may be related to impaired interactions within brain networks, this grant will generate important data describing baseline levels of brain connectivity.
Brain Anatomy and Connectivity; an Endophenotype in Autistic Spectrum Disorder? (Pilot Project Grant)
Declan Murphy, M.D., Kings College, London
There is increasing evidence that people with autism spectrum disorder (ASD) have abnormalities in the way that some brain regions develop, and this may underpin some of the clinical symptoms typically expressed in people with the disorder. The cause of the differences in brain development is unknown - but it is most likely a combination of genetic and environmental factors. However, in people with ASD it is unknown how brain abnormalities are related to genes and/or the environment. Twin studies are a powerful approach for examining the genetic and environmental contribution(s) to brain differences, yet there has been only one prior twin study of brain anatomy in a group of people with ASD. Brain scientists are increasingly aware that it is not just how big, or small, particular brain regions are that is crucial. Equally important is how brain regions are 'connected up' to each other. Nevertheless, nobody has examined how brain connectivity is affected in twins (i.e. what causes brain regions to be ‘wired up' differently in people with autism). It has recently become possible to examine connectivity using a technique called diffusion tensor magnetic resonance imaging (DT-MRI). Thus, the aim of Dr. Murphy's study is to investigate the genetic and environmental determinants of brain anatomy and connectivity in twins with and without ASD by examining specific neural systems implicated in the disorder (e.g., language systems). Dr. Murphy's team brings together experts in autism, genetics, psychology, brain imaging, and behavior. If their efforts are successful, the team plans to initiate large-scale international twin studies using brain imaging in order to help us understand more about the cause(s) of autism.
The Role of Dynamics in Sensory Information Processing: Possible Clues for Autism (Pilot Project Grant)
Mark A. Tommerdahl, Ph.D., University of North Carolina, Chapel Hill
Autism has been described as a neurological disorder that involves abnormal connectivity between different regions of the brain. This functional connectivity between brain regions is quite difficult to study, and most studies currently employ methods that are not only expensive in cost (such as fMRI), but in the amount of time that it takes to observe the interactions that take place between different cortical regions of the brain. To study how functional connectivity differs in individuals with autism, Dr. Tommerdahl is focusing his studies on the cortical-cortical interactions in the regions of the brain that perceive sensory stimuli such as touch. His lab has recently developed novel methods for a non-invasive means of measuring how well cortical regions interact with one another. They will test three different manipulations of touch to the skin in order to obtain perceptual metrics that index how well the cortical regions are interacting and integrating this sensory information. In preliminary studies using this new technology, Dr. Tommerdahl and colleagues have already found that there are significant measureable differences in the integration of information between individuals with autism and those without. This grant seeks to develop a portable stimulator, based on the prototype that he used to collect the preliminary data, and to obtain additional information about the relationship between spatial and temporal sensory integration in normal and autism subjects. It is anticipated that these studies will yield new insights into the differences in functional brain connectivity that exist in individuals with autism. Co-Sponsor: The Gassin Family Foundation
Cellular and Molecular Deficits: Pinpointing the underlying defect(s) in autism
Elucidation and Characterization of the MEF2 Signaling Network and its Relevance to Human Cognitive Function and Autism Spectrum Disorders (Pilot Project Grant)
Michael E. Greenberg, Ph.D., Children's Hospital, Harvard Medical School
The enormous progress in human genetics and the understanding of brain development that has taken place in the last decade now make it possible for the first time to identify the genes and environmental factors that lead to autism spectrum disorders (ASDs), and to articulate testable hypotheses regarding the causes of these debilitating disorders. Dr. Greenberg hypothesizes that ASDs are the result of the disruption of the genetic program that orchestrates the experience-dependent and environmentally affected process of synaptic maturation and refinement. Synapses, the points of communication between neurons, control all learning and memory. Throughout life, visual, auditory, olfactory, gustatory and tactile stimuli initiate cascades of brain activity that creates new synapses and strengthen or weaken existing ones, establishing the neural pathways that underlie learning, memory, and behavior. Dr. Greenberg and colleagues recently identified the MEF2 family as a new class of proteins that might be important for ASDs. They find that the MEF2 family of proteins serves to restrict the number of synapses that a neuron forms. Furthermore, MEF2 proteins associate with a large number of other proteins that have been implicated in ASDs or related cognitive disorders. This project will attempt to identify additional MEF2 interacting proteins with the hope that this will shed light on how disruption of normal synaptic development could give rise to cognitive disorders, as well as identify new molecules that may be involved in ASD, potentially revealing new therapeutic targets. Co-Sponsor: The Gassin Family Foundation
Morphological Reorganization in a Neuroligin-Deficient Autism Mouse Model (Pilot Project Grant)
Frederique Varoqueaux, Ph.D., Max Planck Institute of Experimental Medicine, Germany
The genetic aspects of autism spectrum disorders are complex, and the numerous genetic variations and defects that may contribute are only beginning to emerge. Recent genetic analyses of patients with autism indicate that rare mutations in the genes encoding neuroligin3 and neuroligin4 can be directly linked to autism. Although the mutations in neuroligin genes are likely to explain only a very small percentage of autism diagnoses, they provide a unique opportunity to develop models for the study of the disorder. Dr. Varoqueaux has generated mutant mouse lines in which one or more of the neuroligin genes are eliminated or modified. These will be analyzed with respect to their brain anatomy and connectivity. The investigators will characterize morphological alterations in well-defined, autism-related brain regions using light, fluorescent and electron microscopy. These features will then be compared to the anatomic abnormalities that have been reported in several areas of the autistic brain, for example the hippocampus and the cerebellum. This approach will allow identification of relevant alterations in brain circuitry. The outcome will promote an understanding of the complex dysfunctions observed in patients with autism, and open new avenues towards novel therapeutic approaches that are based on an understanding of the disrupted brain circuitry.
Genetics: Searching DNA for differences that will point to proteins and pathways that may be amenable to treatment
PTEN as a Candidate Gene for Autism Spectrum Disorders (Pilot Project Grant) Vijaya Ramesh, Ph.D. and Susan Santangelo, Ph.D., Massachusetts General Hospital
Despite strong evidence of genetic involvement in autism spectrum disorders (ASD), no specific genes have been identified, which is probably due to the fact that multiple genetic factors may be responsible. However, autism is seen in other genetic diseases such as fragile X syndrome and tuberous sclerosis complex (TSC). TSC is a common neurodevelopmental disorder characterized by abnormal tissue growth known as hamartomas in many organs. Features of autism spectrum disorders are reported to be present in 25-50% of individuals with TSC. For the past several years, Dr. Ramesh's laboratory has been actively engaged in understanding the neurological complication associated with TSC. The TSC genes regulate cell signaling by inhibiting a molecule referred to as mTOR. mTOR signaling plays an essential role in determining how neurons in the brain communicate with each other. Importantly, another key regulator of mTOR signaling is a protein known as PTEN, and intriguingly mutations in the PTEN gene have been identified in a small number of autistic individuals. Furthermore, a very recent study in mice has shown that PTEN deficiency in selective populations of neurons can result in features resembling human autism. Drs. Ramesh and Santangelo hypothesize that inherited variations in PTEN will be associated with genetic risk for ASD. They will test this by examining PTEN mutations in a large cohort of autism patients, including many from the Cure Autism Now AGRE collection, in order to establish a clear role for PTEN in autism. Furthermore, their work has the potential to lay the foundation for abnormal mTOR signaling as one of the causes for autism, providing a new direction for the study of pathogenesis and treatment of autism spectrum disorders. Co-Sponsor: The Gassin Family Foundation
Genomic Instability of an Interval on Chromosome 10q and Its Contribution to Autism Spectrum Disorders (Pilot Project Grant)
Scott B. Selleck, M.D., Ph.D., University of Minnesota
Recently human geneticists have come to understand that quite frequently chromosomes can have deletions (gaps in the DNA) or duplications (replications in the DNA), even in normal people without any known disease. These changes in DNA are not randomly distributed, but are associated with particular features of chromosomes. Dr. Selleck has recently discovered that one such region of instability is found on chromosome 10, where several genes known to be important for normal brain development are located. He hypothesizes that small deletions or duplications occur in this region of chromosome 10 at a high frequency, and sometimes alter the function of genes in the region, making an individual more susceptible to the development of autism. This hypothesis predicts that DNA sequence changes in this chromosome 10 region would be more frequent in autistic children compared to normal controls. In collaboration with a team of scientists in Toronto, Dr. Selleck has just found preliminary data that DNA sequence changes in this region are indeed found significantly more frequently in children with autism compared to children without autism spectrum disorder. With this grant, Dr. Selleck's team will now determine what DNA sequences, and genes, in this region are most commonly affected in children with autism compared to non-autistic controls. To accomplish this they will be using a special DNA chip that allows them to precisely map DNA sequences across this region of chromosome 10. These findings should assist in both understanding the biological mechanisms that are generating autism, and in providing tools for more accurate diagnosis.
Blood Genomic Studies of Children with Idiopathic Autism (Pilot Project Grant)
Frank R. Sharp, M.D., University of California, Davis Autism appears to be a complex neurodevelopmental disorder that may be caused by the interaction of inherited genes with still unknown factors in the environment. One way to measure the expression of genes is to study RNA patterns. Dr. Sharp has demonstrated that RNA expression studied using newly developed microarrays can reliably detect the effects of a given disease on gene expression in the blood. In addition, environmental agents like medications, and infectious agents like bacteria and viruses, also produce characteristic RNA expression patterns in blood. Dr. Sharp has now applied this approach to children with autism ages 2 to 5. The data suggests that there are differences in RNA expression that can distinguish children with early onset autism from children with later onset of autism associated with regression. His data also revealed RNA expression patterns that correlate with high expression of genes associated with Natural Killer (NK) cells and cytotoxic T lymphocytes (CD8+ cells) in peripheral blood. His laboratory will now test whether the genes found to be regulated in children 2-5 years old are also regulated in children 5-18 years old. They aim to confirm that age at onset is related to characteristic blood RNA profiles in children with autism, and that the genes regulated in Natural Killer cells – the cells that normally kill viruses when they enter the blood stream – are also up regulated in a large subgroup of children with autism. This study should help identify different types of autism, and possibly point to abnormalities of NK and/or CD8 cells that might affect the ability of the developing fetus or newborn child to deal with certain types of viruses. In addition to the generous co-sponsors listed above, Cure Autism Now would also like to thank the following supporters for helping make the 2007 Pilot Project and Young Investigator grants possible.
Pilot Project Grant Fund
James, Brenda and John McCoy
Rudy Prio Touzet
Ellen and Jonah Zimiles
Young Investigator Grant Fund
Thomas and Jean Brooks
Interfeld Family Foundation
Anthony and Mary Yorio