Archived | Autism Speaks: 2008 Environmental Factors and Autism 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



David Baskin, M.D.
The Methodist Hospital, Houston
$60,000 for one year


Differential Effects of Thimerosal on Cell Division and Apoptosis in Normal vs Autism Spectrum Disorder Cell Lines

This study will investigate the effects of a dose-dependent exposure of thimerosal on cell proliferation. First, thimerosal will be exposed to immortalized lymphocyte cell lines from autistic and non-autistic individuals as part of the AGRE collection, as well as human B cells.

Autism Genetic Resource Exchange (AGRE)

Both cell number and apoptosis will be examined before and after treatment. These results will be used to examine changes in cell proliferation (cell number) on an individual level with symptoms of autism including severity of disease, recovery, intestinal symptoms, immune function, and vaccination history.

Finally, the RNA will be extracted from the lymphocytes and a whole genome array will be conducted on those lymphocytes with the largest change in cell proliferation, as well as five unaffected siblings. The investigators anticipate that cell proliferation will be a more sensitive measure than apoptosis in detecting differences in susceptibility to mercury exposure in lymphocytes from autistic and non-autistic individuals. The results of this research will facilitate advances in the understanding of the cause of autism.

What this means for people with autism: This study will use the existing AGRE resource to examine if more sensitive endpoints are possible to determine the effects of environmental toxicants on cellular function. By doing so, it will facilitate knowledge into the understanding of the causes of autism.


Betty Diamond, M.D.
The Feinstein Institute for Medical Research
$330,000 over 3 years

The pathogenesis of autism: maternal antibody exposure in the fetal brain

There is abundant evidence that autism occurs in families with evidence of autoimmunity. There is also evidence that mothers of an autistic child may have antibodies that react with brain tissue and even evidence that these antibodies, when given to pregnant mice or pregnant monkeys, cause behaviors in the offspring analogous to aspects of the autistic syndrome.

The investigators will explore the role of maternal antibodies in ASD, identifying maternal sera with anti-brain antibodies, determining if these antibodies can cause brain pathology and neurologic abnormalities in mice exposed to them during pregnancy, characterizing the brain antigen(s) recognized by the antibodies and assessing how frequently these antibodies are present in mothers of an autistic child. This group will also examine children born to mothers with particular maternal antibodies examine the relationship between these circulating antibodies and autism behaviors in the children.

What this means for people with autism: While the investigators are aware that this mechanism of disease may be operative in only a subset of patients, these experiments can determine the validity of this model. These studies may then help identify at-risk pregnancies for future studies of prevention in appropriate individuals. Furthermore, they may help identify the brain injuries, that caused by maternal antibody or by other mechanisms lead to autism.


Bruce Hammock, Ph.D.
University of California at Davis
$158,046 over 2 years

Vitamin D Status and Autism Spectrum Disorder: Is there an association?

This work proposes to explore an association between vitamin D status and ASD diagnosis and severity. In addition to its classical role of proper bone mineralization vitamin D, plays an important role in brain development, cognitive and behavioral function and the suppression of autoimmunity.

Using the CHARGE study at the MIND Institute in California, Dr. Hammock will examine both levels of vitamin D as well as gene variants which control Vitamin D metabolism from mothers, newborn blood spots, children with autism and typically developing controls. They will also examine the relationship between vitamin D status and genetic influences which control vitamin D metabolism.

The study will determine whether there is a difference in prenatal levels of vitamin D, and whether this contributes to later developing autism. Additional variables, such as diet and lifestyle habits will be examined to help explain this relationship.

What this means for people with autism: Twenty years ago scientists advised mothers to keep their children out of the sun as much as possible. Although this led to a decrease in skin cancer, studies now show that approx. 25-57 % (depending on race and season) of adults are vitamin D deficient.

Even if the differences are only social, the broad implications of vitamin D deficiency in bone health, immune modulation and cancer indicate that providing vitamin D status will be of value to the families of autistic children. Further, this information can be used as a basis for future treatment options.


Yong-hui Jiang, M.D., Ph.D.
Baylor College of Medicine
$319,016 over 3 years

Maternal supplementation of folic acid and function of autism gene synaptic protein Shank3 in animal model

The genetic basis of autism has been well established. In addition to changes in DNA structure, other modifications, such as methylation or histone acetylation, may change gene expression in the absence of heritable mutations in DNA.

Previous studies have indicated that environmental toxicants can gene expression through epigenetic mechanisms. Dr. Jiang has been working with a strain of mouse which shows mutations in both SHANK 3 and MTHFR, both implicated in autism spectrum disorder. He hypothesizes a link between folic acid and DNA methylation of SHANK3, producing abnormal gene expression. His lab will use this animal model to study whether administration of folic acid will increase 5-methylenetetrahydrofolate(5-MTHF) and cause DNA hypermethylation of synaptic protein like SHANK3. Changes in the methylation status of these genes would not change the structure, but may change the function of the gene such that differing levels of protein are produced, altering brain function and synaptic plasticity.

Folic acid has been proven to reduce the incidence of major birth defects and is an important component of prenatal vitamins, however, this study will examine whether some mothers may be vulnerable to high doses of folic acid due to genetic variants of this pathway.

What this means for people with autism: Because of the beneficial effects known to taking folic acid during pregnancy, this animal study will provide insight into the mechanisms by which folic acid affects the brain. It will also use new technologies to examine the role of epigenetics modifications of DNA in autism, and study the interaction between methylation of DNA and a gene implicated in ASD: SHANK3.


Flavio Keller, M.D.
Università Campus Bio-Medico di Roma
$324,340 over 3 years

Analysis of developmental interactions between Reelin haploinsufficiency, male sex, and mercury exposure

This project will investigate the role of three separate factors in an animal model of autism spectrum disorder: a) genetic susceptibility, b) hormonal environment, and c) possible environmental triggers.

A mouse model with a mutation of the reelin gene, implicated in autism spectrum disorders, will be studied after exposure to methyl and ethyl mercury. Both behaviors and neuropathological endpoints will be explored.

Finally, the role of endogenous sex hormones will be examined by eliminating the testosterone “surge” around the time of puberty. The individual effects of each will be examined, as well as the interaction of the three components (genetic liability, environmental exposure, hormonal influences) to determine gene x environment interactions.

What this means for people with autism: This study will use a unique design to study multiple factors in the etiology of autism spectrum disorder in a mouse model, isolating and combining factors which previously have been implicated in the pathophysiology and behavioral phenotype.


Janel LeBelle, Ph.D.
UCLA
$211,200 for 1 year

Interactions of environment and molecular pathways on brain overgrowth in autism: Maternal inflammation and the PI3/AKT pathway

It has been recently reported that some individuals with autism show premature brain overgrowth early in development. This may be the result of more brain cells, improved cell survival, or larger cell size in the developing brain. It may also be the result of specific genetic mutations such as PTEN or the Tuberous Sclerosis genes.

Recent studies have demonstrated that brain overgrowth can also be caused by the interaction of environmental factors such as maternal inflammatory response (MIR) with genetic susceptibility during periods of vulnerability in fetal development. Here, we seek to understand mechanisms of MIR-induced macrocephaly in ASD.

One mechanism by which genes and environment might interact in maternal inflammatory response is through the production of reactive oxygen species (ROS). While it is well known that high levels of ROS are toxic to cells, the effects of low levels of ROS are unknown. Maternal and embryonic ROS levels can be influenced by many environmental factors including viral infection and allergic/immune disorders which have also been positively associated with macrocephaly.

This lab has previously shown that low levels of ROS produced by NOX enhance neural stem cell self-renewal, at least in part due to disruption of PTEN function. Here, they will determine whether there is a pathogenic link between NOX generated ROS and brain size in a rodent model.

What this means for people with autism: If environmental factors result in a maternal immune response by inducing NOX and producing levels of ROS that reversibly inactivate PTEN, this inactivation of PTEN could be responsible for a widespread prevalence of brain overgrowth in autism.

This can lead to potential therapeutic responses that reduce reactive oxygen species generation and possibly prevent brain overgrowth and affect PTEN signaling, perhaps partially preventing autism symptoms in some individuals at risk for autism. 


Sandra Mooney, Ph.D.
SUNY Upstate Medical Center
$330,000 over 3 years

Social behavior deficits in autism: role of amygdala

The model we propose to examine (prenatal exposure to sodium valproate) has been shown by others to result in changes in social and other behaviors that are similar to those seen in people with autism. We plan to focus on the biology, that is, to determine what changes in the brain underlie the behavioral deficits.

Data generated during this study will add to the understanding of how changes in the brain contribute to social behavior. Determining exactly which brain regions underlie the social behavior deficits will allow clinicians to focus on imaging those specific parts of the brain to diagnose autism, and early and accurate diagnosis improves prognosis. Understanding the regions of the brain important for social behavior, and how changes in the gene expression, structure, and function of those regions affect social behavior will provide novel targets for therapeutic interventions such as oxytocin.

Finally, understanding which particular times of pregnancy the developing brain is especially vulnerable will allow physicians to better manage care of their patients, as well as allowing them to inform their patients regarding the risks associated with taking drugs at those times.

What this means for people with autism: Using VPA as a model, this study will provide information to scientists and clinicians to better understand the critical time periods by which environmental exposures may produce the most deleterious effects, and offers a potential pharmacological treatment which in the future could be used in the clinic for individuals with autism spectrum disorders.


Mark Noble, Ph.D.
University of Rochester
$330,000 over 3 years

Vulnerability phenotypes and susceptibility to environmental toxicants: from organism to mechanism

One hypothesis regarding the association between genetic changes, environmental factors and autism is that many mutations or polymorphisms make the organism more vulnerable to later exposure in some individuals.

Called the “vulnerability phenotype”, the Noble lab hypothesizes that one potential unifying theme of the vulnerability phenotype of children with ASD is that they are more oxidized. This elevated oxidation state has been shown to be sufficient to cause dramatic changes in cellular function. In this project, Dr. Noble will test the hypotheses that genetically-based differences in oxidative status are associated with differences in vulnerability to physiological stressors in vitro and in vivo, with even greater increases in vulnerability to combinations of physiological stressors.

Specifically, thimerosal and other vaccine adjuvants will be studied. The second part of the study will determine if these effects on a novel regulatory pathway called redox/Fyn/c-Cbl is a necessary mechanistic convergence for increases in vulnerability caused by a more oxidized metabolic status. These results will provide a better understanding of the biochemical effects and mechanisms of possible toxicity of vaccines and vaccine additives.

What this means for people with autism: These studies will initially focus on the combination of vaccine additives, but then examine whether a background genetic vulnerability phenotype affects the response to these additives.

The results would provide new targets for intervention against the adverse effects of increased oxidative status in children with autism.


Robert Plomin, Ph.D.
Kings College of London, Institute of Psychiatry
$304,422 over 3 years

Identical twins discordant for autism: Epigenetic (DNA methylation) biomarkers of non-shared environmental Influences

There has been much research into the genetic causes of autism, driven in part by the concordance rate in twins. However, the fact that some pairs of identical twins differ in autistic symptoms makes clear that there must be an important non-genetic (i.e., environmental) component as well that can differ even within a family (called non-shared environment).

There is much speculation on what these non-shared environmental factors might be, and need a way to identify them and the mechanisms by which they contribute to autism. This project will move this field forward by investigating a major biological mechanism that can retain a long-lasting impression of the environment and which regulates gene expression: DNA methylation, a form of epigenetics similar to the work in Dr. Jiang’s lab.

Dr. Plomin’s lab will study DNA methylation in a twin cohort called the “twins early development study” using new technology to study the whole genome. First, this lab will examine differences in DNA methylation across identical twins discordant for autism. These differences can be caused by a “nonshared” environment within a family.

In addition, they will study whether these differences are seen between those affected with autism and unrelated cases who are not diagnosed. Finally, the Plomin lab will examine epigenetic markers that differ in individuals who show a social vs. non-social phenotype. The proposed biological index of non-shared environmental influence will be a vital starting point for mapping out the environmental causal pathways that lead to ASD, which have special value because risky environments could be prevented or reversed more easily than risky genotypes.

What this means for people with autism: The proposed biological index of non-shared
environmental influence will be a vital starting point for mapping out the environmental causal pathways that lead to ASD, which have special value because risky environments could be prevented or reversed more easily than risky genotypes.

Because identical twins show identical DNA, areas of methylation on the DNA are an increasingly researched area to determine gene x environment interactions in autism and other disorders, and how one twin may manifest symptoms differently than the other.


Nicholas Ponzio, Ph.D.
UMDNJ
$330,000 over 3 years

Influence of maternal cytokines during pregnancy on effector and regulatory T helper cells as etiological factors in autism

Despite the specific genes or environmental exposures which may contribute to ASD, one theme that emerges from clinical and experimental studies is inflammation and autoimmunity in individuals with ASD and their families.

Such an immune response may be the consequence of genetic and environmental interactions leading to pathophysiology and symptomatology of the disorder. In order to better study the immune response, Dr. Ponzio and his colleagues propose to use well-documented experimental models of ASD to test the hypothesis that stimulation of the maternal immune system during pregnancy alters the normal proportions of newly discovered populations of lymphocytes known as T Helper 17 (TH17) cells and T regulatory (Treg) cells, the balance of which may be responsible for determining whether or not the observed neuroinflammation in ASD occurs.

Activation of specific types of lymphocytes during an immune response causes secretion of proteins (known as cytokines) that can induce inflammation. If this occurs during pregnancy, these cytokines may cross the placenta, enter the fetus, and influence neural development and cause immunological outcomes and ASD-like behavior patters in the offspring.

This experiment will examine different mechanisms by which cytokine secretions may mediate neural development, including whether or not they alter the placenta, whether they can enter fetal tissues, and if they promote differentiation of immune cells which alter the neuroinflammatory process.

What this means for people with autism: A better definition of the induction and function of Th17 and T regulatory (Treg) cells is critical in understanding the pathogenesis and regulation of inflammatory disorders and autoimmunity and will elucidate immunological mechanisms that may be triggered by environmental factors that promote the development and pathogenesis of ASD.


Emile Rissman, Ph.D.
University of Virginia
$300,000 over 3 years

Epigenetics, hormones and sex differences in autism incidence

Across studies, the ratio of male to female affected with autism is approximately 4:1. This striking sex difference has been seen consistently. Basic research on sex differences in behavior has shown that differences in circulating levels of gonadal hormones during fetal and infant development are responsible for most sexual dimorphism in adults.

For normal male development to occur, sex hormones like testosterone act through estrogen receptors, which in turn also activate other genes and proteins. The activation of certain genes through estrogen receptor, then, may partially explain the sex difference.

The body produces natural testosterone and estrogen that a normal body produces, but environmental chemicals may mimic these compounds and produce deleterious effects during development. For example, a chemical called Bisphenol A, has been used as a plasticzer agent and is found in beverage bottles, and other plastic products has several actions; as an estrogen agonist or antagonist, or as an anti-androgen and as a disruptor of hormone biochemical pathways.

It is also a DNA hypomethylating agent and thus affects transcription of other genes. In the past year consensus statements from the scientific community express concern that this compound acts via a number of mechanisms on the brain during development. This study will use estrogen receptor knockout mice to determine sex-differences on many autism like behaviors in mice, and identifying genes which are affected by BPA, in order to identify the mechanism of action of this environmental chemical, and whether it may be linked to autism.

What this means for people with autism: Dr. Rissman and her colleagues will not only explore the role of Bisphenol A in autism, but determine the mechanism by which sex hormones may interact with environmental agents during critical periods in development.

It will also further explore the role that modifications of the “epigenome” may result in abnormal behaviors, opening the door for researchers examining other exposures of interest.


Judy Van De Water, Ph.D.
University of California at Davis
$659,100 over 3 years

Etiology of Autism Risk Involving MET Gene and the Environment

Two independent lines of evidence indicate that the maternal immune system and a functional genetic variant contribute to autism spectrum disorder (ASD) risk. Here, in a unique collaborative effort, the Van De Water lab will parter with scientists at Vanderbilt University to examine whether these two seemingly unrelated contributions may converge to define a unique ASD susceptibility.

Preliminary evidence collected by the Van De Water lab indicates an association between the MET gene ‘C’ type, which reduces MET protein expression, and the presence of specific maternal anti-fetal brain autoantibodies. This relationship suggests that this as a pathway for production of the maternal autoantibodies, leading to a gene x environment interaction underlying ASD susceptibility.

The next line of experiments will examine the relationship in an even larger sample, and assess the functional effect of the MET gene polymorphism on immune cell activity, and to further examine the impact of environmental toxins (including ethyl mercury) on the gene expression-dependent function of maternal immune cells.

What this means for people with autism: This proposal thus brings together two initially unrelated findings (associations of the MET gene and maternal autoantibodies with ASD), and further tests specific functional hypotheses concerning gene-environment interactions, that may converge to define a unique cause of autism in some children.



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