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Research Funding for 2004
Table of Contents
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Research Summary: National Fragile X Foundation Clinical Grant
David Hessl, Ph.D. - $30,000
M.I.N.D. Institute and Department of Psychiatry and Behavioral Sciences
U.C. Davis, Sacramento, CA
Hyperarousal and Aggressive Behavior in Fragile X Syndrome
Resulting Publications:
- Journal of Autism and Developmental Disorders (2006)
Research Summary: National Fragile X Foundation Clinical Grant
Patricia J. Gammon, Ph.D. - $30,000
Duke University Child and Family Study Center
Manifestations of Anxiety in Children with Fragile X Syndrome
Research Summary: National Fragile X Foundation Clinical Grant
Jane Roberts, Ph.D. - $30,000
FPG Child Development Institute
University of North Carolina at Chapel Hill
Molecular-Clinical Correlates in Fragile X Syndrome
Research Summary: National Fragile X Foundation Basic Science Grant
Jason B. Dictenberg, Ph.D. - $30,000
Cytoskeletal-dependent trafficking of FMRP and target mRNAs to neuronal synapses: a role for FMRP as
an adapter between localized mRNAs and molecular motors
Resulting Publications:
- Mechanism may explain aspects of brain impairment seen in Fragile
X Syndrome (2008)
Research Summary: National Fragile X Foundation Basic Science Grant
Frank Kooy, Ph.D. - $30,000
Is the GABAA receptor a therapeutic target for the Fragile X Syndrome?
Resulting Publications:
- Brain Research (2006)
Research Summary: National Fragile X Foundation Basic Science Grant
Rob Willemsen, Ph.D. - $30,000
Role of Intranuclear Neuronal Inclusions in the Pathogenesis of the FXTAS
Resulting Publications:
- Behavioural Brain Research (2005),
- Current Neurology (2005)
Summer Student Fellowships
Research Summary: National Fragile X Foundation Clinical Grant
David Hessl, Ph.D. - $30,000
M.I.N.D. Institute and Department of Psychiatry and Behavioral Sciences
U.C. Davis, Sacramento, CA
Hyperarousal and Aggressive Behavior in Fragile X Syndrome
Aggressive and destructive behavior is a significant problem for approximately 50% of males and 20% of females with fragile X
syndrome. This problem may begin or worsen in the post-pubescent period, when the combination of aggression, increased physical strength and development of teens and young adults can pose a serious threat to peers, family
members, other care providers, and to the patients themselves when self-injury is involved. From the standpoint of many clinicians and parents, aggressive outbursts are often precipitated by sensory stimuli in the environment
that the patient is overwhelmed by, leading to hyperarousal, irritability, and finally an aggressive outburst. This behavior may also be precipitated by anxiety, which is a very common problem especially in novel social
situations or when changes in routine occur. Individuals with fragile X also may be especially susceptible to the influences of other genetic or family environment factors that are linked to anxiety and aggression. An
understanding of these influences would be especially useful in guiding treatment that could be focused on regulating emotion through behavioral or pharmacological treatment versus modulating sensory input versus family-level
intervention.
This study will examine the effects of physiological hyperarousal (heart rate, sweat response), anxiety, sensory reactivity, and family environment on aggression in males with the fragile X full
mutation, ages 12 to 25 years. In addition, the impact of other genes documented to be associated with anxiety and aggression (serotonin transporter and monoamine oxidase A polymorphisms) in the general population will be
studied in these individuals. Note that the study will include individuals with and without significant aggression. Please contact Dr. David Hessl (david.hessl@ucdmc.ucdavis.edu; 916-703-0249) or Lisa Cordeiro lisa.cordeiro@ucdmc.ucdavis.edu ; 916-703-0353) for more information.
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Research Summary: National Fragile X Foundation Clinical Grant
Patricia J. Gammon, Ph.D. - $30,000
Duke University Child and Family Study Center
Manifestations of Anxiety in Children with Fragile X Syndrome
Fragile X syndrome affects children's learning, behavior, and emotions. One set of emotions which often interferes with children's lives
is anxiety and worry. At Duke, we will be combining the expertise of our Fragile X Clinic and our Pediatric Anxiety Disorders Clinic to study the emotions of anxiety, fear and worry in children with FXS. Combining the
knowledge and experience of Ave Lachiewicz, MD, in Developmental Pediatrics and myself, Patricia Gammon, Ph.D. in Child Psychology, we will be developing ways to better understand these emotions in boys and girls between the ages
of 7 and 18 who have Fragile X Syndrome.
We are particularly concerned that many children with FXS may have a harder time learning as they grow older because of increasing anxiety. If they are uncomfortable around
other children, fear going to school, and avoid new situations, they will have more difficulty learning both in school and from the world around them. Therefore, we will enlist the help of mothers of children with FXS to help
us learn about what their children are frightened of and worried about. We also want to hear about how their children demonstrate these fears and worries, and what their children may experience when distressed. Moms will
complete standardized, state of the art measures of their children's anxiety to help us develop an in-depth understanding of how anxiety is similar and different from children who do not have FXS. We will also interview
Moms to obtain further understanding of the unique emotional concerns of these children. Dr. Lachiewicz will be working on a parent report checklist to aid pediatricians in efficiently obtaining information on the anxieties of
these children.
Not only do we want to characterize Mom's reports of the nature, severity, and frequency of fear and anxiety in their children, but we also want to hear from the children themselves. Therefore,
we will be developing a picture tool to help children with FXS communicate to us about these feelings and emotions. Using information from the checklists and interviews with Moms, we will be developing a pictorial tool to help
children share what situations are scary or troubling to them, and how they react to anxiety-provoking situations. Before we can fully help children deal effectively with their fears and worries, we believe it is important to
have a means of effectively communicating with them about these emotions.
Our long range goal is to develop simplified treatment strategies to use with children with FXS who are troubled by anxiety and/or
fears. Both guidance for parents and interventions with children will be important. The effectiveness of such behavioral interventions and medications can best be evaluated if we have helpful protocol for evaluating
children's worries and emotional distress.
The NFXF would like to thank its Richard Kurtz MD Memorial Research Fund for support of this project.
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Research Summary: National Fragile X Foundation Clinical Grant
Jane Roberts, Ph.D. - $30,000
FPG Child Development Institute
University of North Carolina at Chapel Hill
Molecular-Clinical Correlates in Fragile X Syndrome
This project is a joint effort between the Carolina Fragile X Project and the Carolina Communication Project, a series of collaborative longitudinal studies at
the FPG Child Development Institute at the University of North Carolina at Chapel Hill under the direction of Don Bailey. Completion of this project will allow us to accomplish two important goals. First, it will allow us
to have a large sample of molecular data on young children with the full mutation of fragile X syndrome (FXS) and their carrier mothers. Second, it will allow us to examine the relationship of cognitive and social-behavioral
features in these individuals to multiple molecular measures including FMRP, mRNA, CGG repeat length, and methylation status in males and females plus activation ratio in females.
Recent research findings have
dramatically changed our biological understanding of the way in which the FMR1 gene functions. This work suggests that multiple molecular variables are involved in a complex system of inter-related functions. These recent
biological findings suggest that some of the wide variability of behavioral, cognitive, and social-emotional effects seen in many persons with the full and premutation of FXS may be related to one or more molecular
variables. However, the previous work has focused on individuals with the full mutation and FMRP expression. Little work has been done examining multiple molecular measures in persons with the full mutation and few
studies have examined molecular measures in persons with the premutation.
Previous work has focused on FMRP expression in persons with the full mutation. While this work indicates a relationship between
higher expression of FMRP and improved cognitive, behavioral, and physical features in FXS, the relationship between FMRP and FXS features is not always strong, and some studies have not found a relationship between FMRP and
features of FXS. Recent work has focused on molecular function in persons with the premutation, and one very important finding in this work is documentation of elevated mRNA. This finding is important because early
reports described individuals with the premutation as having subtle or no effects of FXS yet more recent studies have shown that some individuals with the premutation may have physical, cognitive or social-emotional
effects. While there are a few studies that have described a relationship between greater CGG repeat length, lower FMRP, and lower activation ratios in persons with the premutation to difficulties with cognitive processing and
social-emotional difficulties, no studies have examined these relationships with mRNA. Furthermore, no work has examined which molecular measure or combination of molecular measures best correlates with outcomes in children with
the full mutation or carrier women.
While we have learned a great deal about the molecular features of FXS, more work needs to be done to examine the relationship of these molecular variables to specific
cognitive, behavioral, and social-emotional features in FXS. Knowledge regarding the relationship between molecular variables and effects in FXS is critical for proper diagnosis and therapeutic intervention.
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Research Summary: National Fragile X Foundation Basic Science Grant
Jason B. Dictenberg, Ph.D. - $30,000
Cytoskeletal-dependent trafficking of FMRP and target mRNAs to neuronal synapses: a role for FMRP as an adapter between localized mRNAs and molecular motors
The basic unit of the brain, the neuron, is the most polarized
cell type in animals. Unlike most cells that are relatively spherical in shape, the neuron is extremely elongated and therefore is able to transmit signals from inside the cell over large distances toward other far away neurons.
The point of contact between these neurons is a specialized structure termed the synapse, where the release of chemical signals from the activated neuron directly onto the signal-receiving neuron changes the action of proteins
located at the synapse. FMRP is one of these proteins that act in response to chemical signals to maintain the activity of the synapse and modify the protein composition there over extended periods of time. Recent research has
highlighted the importance of local translation of proteins in response to chemical signaling in neurons, that is, the synthesis of new proteins within a specific area such as the synapse. FMRP appears to play a central role in the
regulation of translation of these localized mRNAs at the synapse.
All proteins are translated from an mRNA that codes for that specific protein, and the mRNA is made as a copy of a gene contained in DNA that is restricted
to the nucleus of the cell, located at the center of the neuron far away from the synapse. In order for the mRNA to reach the distant synapse where its translation into protein can be locally regulated, it first has to be
transported to that site. Since FMRP binds to several synaptically localized mRNAs, and this binding can inhibit the translation of the mRNA, FMRP represents a good candidate for a transport "chaperone" that could bind to the mRNA
after it is synthesized in the nucleus and repress its translation until it reaches the distant synapse. In fact, FMRP has been observed to move within living cells from the nucleus toward the synapse. Preliminary data from our lab
suggests that FMRP can bind to intracellular "motors" that function to transport cargoes within the cell from one place to another. Therefore our working hypothesis is that FMRP acts as an adapter protein between the mRNAs destined
for the synapse and the motor proteins that transport intracellular cargoes. Under conditions where FMRP is absent, such as in Fragile X syndrome, the loss of such an adapter protein predicts that these mRNAs would no longer be
efficiently transported to the synapse and result in a lower level of the protein which they encode at synapses, possibly explaining the observed changes in synaptic activity of Fragile X neurons. Strong precedence exists for this
type of mRNA "mis-sorting" in the absence of RNA-binding proteins that regulate mRNA translation from extensive research on embryonic development. Using a combination of genetics, biochemistry and state-of-the-art cell biological
imaging techniques my work aims to elucidate the role of FMRP in transport of mRNAs to which it binds, and to identify the specific motor proteins that are responsible for the movement of FMRP and mRNAs to synapses. A better
understanding of the molecular defects that underlie Fragile X syndrome will enable future studies to focus on how to design effective therapies for the disease.
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Research Summary: National Fragile X Foundation Basic Science Grant
Frank Kooy, Ph.D. - $30,000
Is the GABAA receptor a therapeutic target for the Fragile X Syndrome?
FMRP,
the protein missing in the fragile X syndrome is an RNA binding protein that, in specific brain cells called neurons may play a role in local protein synthesis. Though a wealth of scientific information has been gathered about the
function of the fragile X protein, the central question as to why absence of the protein causes mental retardation and additional symptoms of the disorder remains unanswered as yet.
In order to identify novel pathways
possibly involved in the fragile X syndrome, we have recently performed gene expression profiling of the fragile X knockout mouse model, shown to be a valid animal model for the fragile X syndrome. The rationale behind our
experiments is that genes that are over or underexpressed in the fragile X syndrome might indicate which pathways are involved in the pathogenesis of the fragile X syndrome. Using differential display, we found reliable,
reproducible differences in gene expression between knockout and control littermates limited to a few genes only. Among the genes we identified was the gene encoding the δ subunit of the γ-aminobutyric acid type A (GABAA)
receptor, the main inhibitory receptor in the brain.
This finding is of significant interest, as GABAA receptors have been implicated in anxiety, epilepsy, and learning and memory. Interestingly, numerous drugs of clinical
importance bind to the various types of the GABAA receptor, including benzodiazepines like diazepam (Valium®) and chlordiazepoxide (Librium®) that bind to the α and δ subunits and barbiturates, such as
Phenobarbital, that bind to the α and ß subunits. At this moment, we do not know whether underexpression of the receptor subunit in the fragile X mouse model is related to the symptoms of the disease, whether expression of
subunits in addition to the δ subunits is affected, nor whether underexpression can be demonstrated in human patients. The NFXF grant will allow us to find answers to these intriguing questions in the year to come!
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Research Summary: National Fragile X Foundation Basic Science Grant
Rob Willemsen, Ph.D.
Role of Intranuclear Neuronal Inclusions in the Pathogenesis of the FXTAS
Carriers of the fragile X premutation are generally thought to lack the characteristic phenotypic manifestations associated with the fragile X
full mutation. However, the description of a new neurological disorder involving progressive intention tremor, gait ataxia and Parkinsonism in some older PM carriers led to the identification of the fragile X-associated
tremor/ataxia syndrome (FXTAS). Recently, we generated a "knock-in" mouse model for FXTAS and reported neurohistological, biochemical and molecular studies of the brains of this mouse model. Pathologically, the presence of neuronal
intranuclear inclusions has been described in both symptomatic PM carriers and the FXTAS mice. Whether the formation of inclusions underlies the clinical symptoms remains unsolved. It is hypothesized that elevated levels of
abnormal (expanded-CGG repeat) FMR1 messenger-RNA underlies the neurological disorder.
The overall aim of this proposal is to study the role of neuronal intranuclear inclusions in the pathogenesis of FXTAS which could
provide an approach for therapeutic intervention of FXTAS. In addition, although FXTAS occurs by a different mechanism from the fragile X syndrome, it is caused by a mutation within the same FMR1 gene, and therefore opens new
avenues to understanding the FMR1 gene and the fragile X syndrome. Finally, the recent description of a small number of female premutation carriers, who suffer from FXTAS prompted us to focus our studies on the presence of
neuropathology in female mice as well.
The FXTAS mouse model will facilitate molecular studies from onset of symptoms until final stage of the disease, whereas studies on human post-mortem brains will only allow studies at
the final stage of the disease. We believe that studies on "early affected" brain material are essential to understand the formation of the inclusions. Such knowledge may lead to indications how and where the inclusions originate.
Non-invasive MRI of the central nervous system of the expanded-repeat mice will be applied to study subtle abnormalities from onset of symptoms until the final stage of the FXTAS. Alternatively, we would like to develop cell
culture systems to study inclusion formation in vitro.
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Summer Student Fellowships
Awards from the National Fragile X
Foundation do not just go to established researchers and institutions, they are also made to promising students who have demonstrated an interest in fragile X syndrome. These $2500 "Summer Fellowship" grants are made
possible by the William and Enid Rosen Research Fund, the Harry LeCover Memorial Fund and the National Fragile X Foundation Research Fund. Recipients in 2004 were:
- Annie Ngoc Long, UC Davis M.I.N.D. Institute – The William & Enid Rosen Research Fund
The prevalence of fragile X premutation and full mutation
- Danielle Ostfield, McGill University - The William & Enid Rosen Research Fund
Attentional Control and Inhibitory Impairments in Males with Fragile X Syndrome
- Jaskarn Johl, Lake Erie College of Osteopathic Medicine - The William & Enid Rosen Research Fund
High resolution MRI and stereologic analysis currently available of post-mortem formalin-fixed pontine sections from male
& female premutation carriers of FX
- Maria Hopkins, University of Alabama at Birmingham - The William & Enid Rosen Research Fund
An investigation of children with fragile X syndrome and/or autism ability to recognize facial expressions of emotion
- Micah Kradin, UC Davis M.I.N.D. Institute - The Harry LeCover Memorial Research Fund
Analyzing the common traits seen in male proband and non-proband fragile X premutation carriers that are under the age of 18
- Janette Dill, Frank Porter Graham Child Development Institute, University of North Carolina - The William & Enid Rosen Research Fund
Physiological Underpinnings of Sensory Modulation in Toddlers with Fragile X
- Neha Bhatia, Johns Hopkins School of Medicine - The William & Enid Rosen Research Fund
Math, Visuospatial and Working Memory Skills in Girls with Fragile X Syndrome
- Marie DeBernardis, Montana State University – The National Fragile X Foundation Research Fund
Teaching basic math, money and geography skills to children with fragile X syndrome
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