Home/Randi J. Hagerman Summer Scholar Research Awards
Randi J. Hagerman Summer Scholar Research AwardsHilary Rosselot2024-02-20T10:59:35-05:00
Randi J. Hagerman Summer Scholars Research Awards
The Randi J. Hagerman Summer Scholars Research Awards are meant to introduce undergraduate students or students in professional training programs to research in the Fragile X field. We do this by providing funding for summer projects that add to the body of knowledge around Fragile X in a meaningful way while providing a distinct training experience for the Summer Scholar.
The National Fragile X Foundation funds one or more summer student research projects. The work can be in the area of:
Projects can be new or existing. Once completed, each awardee summarizes their summer project in a 15-minute video presentation.
About the Randi J. Hagerman Summer Scholars Research Award
Dr. Randi J. Hagerman is a highly regarded professional within the Fragile X community and a co-founder of the National Fragile X Foundation.
Dr. Hagerman’s knowledge, generosity, and incredible dedication to Fragile X have benefited both professionals and families alike. She has mentored countless professionals within various programs at the UC Davis MIND Institute↗ from all around the world — and has inspired other researchers and clinicians in Fragile X to do the same. Her dedication to mentorship and developing the next generation of professionals in the Fragile X field is truly remarkable.
The goal of the Summer Scholars program has always been to add to the body of knowledge around Fragile X in a meaningful way while providing a distinct training experience for future clinicians and scientists. Dr. Hagerman’s actions have contributed to the unmatched culture of collaboration in Fragile X today.
In the spirit of mentorship and collaboration, the NFXF Summer Scholars program proudly bears Dr. Randi Hagerman’s name.
“The Fragile X field has taught me about the unifying themes across all aspects of clinical medicine and molecular biology throughout the lifespan,” said Dr. Hagerman. “I am honored to have my name associated with the summer student fellowships and I have learned that educating researchers early in their career about Fragile X is the key to influencing their future work because the Fragile X field is so very exciting. The future of the Fragile X field is dependent on these emerging new researchers and this program has put us in good hands.”
We also heard from a few of Dr. Hagerman’s many mentees and colleagues:
Randi Hagerman is a medical doctor with a brilliant mind and a huge heart. She is making a historical shift in the field of Fragile X and has been bringing hope and happiness into many families worldwide. She is always eager to share her knowledge and scientific ideas, thus it is privilege to have Dr. Hagerman as a mentor.
—Dr. Dragana Protic, Belgrade Serbia
Randi Hagerman is a bright shining light and a pillar of strength for the Fragile X community. Her tireless dedication to this cause and relentless pursuit of making a difference to the thousands of individuals with Fragile X and their families will never be surpassed. It is a privilege to meet, work with, and learn from Randi and I will always remember her generosity and passion.
—Dr. Ramkumar Aishworiya, Singapore
Over many years, I have watched Randi Hagerman guide students, post docs, and visiting international scholars, and inspire them toward a lifelong career interest in Fragile X. Because of that, compassionate and informed care is available to many more families that, otherwise, would not have existed.
—Robby Miller, National Fragile X Foundation & UC Davis MIND Institute
The Electroretinogram and FMRP: Correlating Biomarkers for Fragile X Disorders
Affiliation: Senior at the University of California, Davis, majoring in Global Disease Biology and minoring in History
Supervisor: Dr. Dr. Randi J. Hagerman, University of California, Davis, Developmental and Behavioral Pediatrics
Project Summary:The Electroretinogram and FMRP project will assess whether electroretinograms, which measure the activity of the retina, can be used as a reliable marker to detect deficits in FMRP in both those with FXS and those with premutation involvement. The b-wave deficits in the ERG may also correlate with other behavior problems and help us understand how BK channel deficits relate to the phenotype of FXS and premutation involvement. The study will involve a series of questionnaires and assessments, a clinical ERG reading, and molecular analyses. This study can potentially lead to an easy and quick way to screen for Fragile X involvement or FMRP deficits and how this affects behavior.
in their own words
“I worked with Dr. Randi Hagerman at the UC Davis MIND Institute during my final year as an undergraduate at UC Davis. During my fellowship I had the unique opportunity to interact directly with the Fragile X community through my work as a clinical researcher. I obtained electroretinogram readings, learned how to quantify FMRP levels in blood samples, administered sensory and adaptive questionnaires, and recognized the significance of BK channel function in those with Fragile X. I have come to learn the Fragile X community is based on a strong foundation of teamwork and support. The mentorship I received through the summer fellowship allowed me to develop my professional skills in research and appreciate the importance of interdisciplinary collaboration. The cutting-edge research at the MIND Institute represents hope and possibility for the Fragile X community. I am so grateful to have had the chance to work with Dr. Randi Hagerman and the NFXF towards the shared goal of improving the lives of those affected by Fragile X.”
—Aditi Mahajan, UC Davis MIND Institute
FXPOI Survey in Women’s Healthcare Providers
Affiliation: First-year student in the Emory University Genetic Counseling Training Program
Supervisor:Emily G. Allen, PhD, Emory University, Department of Human Genetics
Project Summary: Patients with Fragile X-associated primary ovarian insufficiency (FXPOI) have been reported to have a long period of time between the onset of symptoms and receiving a diagnosis, with an average time of over a year. FXPOI is defined as menopause before age 40 caused by a premutation in the FMR1 gene. Several patients have reported having to bring educational materials to their providers because they were unaware of Fragile X-associated disorders. The goals of this study are to identify the current knowledge base of FXPOI in women’s healthcare providers and to see if provider demographics affect their knowledge of FXPOI as well as to identify POI related genetic testing and carrier screening patterns in their practice.
in their own words
“Our study aims to identify where gaps in knowledge of Fragile X-associated primary ovarian insufficiency (FXPOI) lie amongst women’s healthcare providers including physicians, advanced practice nurses, and medical students. Past studies have found that the average time to a FXPOI diagnosis after symptoms begin is over one year. Additionally, patients have reported bringing educational materials to their providers because they were unaware of Fragile X-associated disorders.”
“This summer, we distributed a survey via email to women’s healthcare providers and at a conference targeted toward OBGYN providers that assessed FXPOI knowledge, familiarity with primary ovarian insufficiency, reproductive carrier screening practices, and genetics exposure. By identifying these gaps in provider knowledge, our goal is to shorten the time to FXPOI diagnosis and improve quality of care for FXPOI patients and their families through provider-focused educational materials that will be created as part of a future project.”
—Alexandra Singleton, Emory University
The Biological Basis of Pragmatic Language in Fragile X Premutation Carriers
Affiliation: First-year doctoral student within the Clinical Psychology program at the Northwestern University Feinberg School of Medicine
Supervisor: Dr. Molly Losh, Northwestern University, Communication Sciences and Disorders
Project Summary:Pragmatic language, or how we use language in social contexts like conversations, is a complex language skill that allows us to build relationships and connect with others. Individuals with fragile X syndrome have difficulties with pragmatic language and often, people with the fragile X premutation (PM) have differences in how they use pragmatic language. Despite this, little is understood about the biological and genetic foundations of pragmatic language skills in women with the PM. This project aims to understand how biological factors might influence pragmatic language skills in PM carriers. To do this, we will examine the relationship between FMR1 genetic variation, a measure that indicates how the brain hears and represents sound, and pragmatic language abilities. Through this research, we hope to gain insight into the causes of language differences in FMR1 conditions. By understanding the root of these differences, we may be able to develop target language interventions, as well as investigate the relationship between pragmatics and clinical disorders experienced by many PM carriers such as anxiety and executive function difficulties, ultimately creating a path towards targeted treatment.
in their own words
“Participating in the National Fragile X Foundation Randi J. Hagerman Summer Scholars Award has been a truly incredible experience. The program has provided me the opportunity to conduct exciting, innovative research investigating the biological bases of social communication abilities in women who carry the FMR1 premutation. Through this work, I have started examining the biological foundations of prosodic synchrony, an important skill involved in social communication, through the novel application of a statistical analysis that incorporates the temporal dynamics of speech. The preliminary results discussed in my presentation show that this methodology may be sensitive in detecting subtle language differences in premutation carriers. This is a vital first step in developing social communication interventions for individuals with FMR1 conditions that the target underlying causes of language difficulties. As I continue to advance this project, I hope to publish my results in an academic journal. Not only has the Randi J. Hagerman Summer Scholars program given me with the opportunity to initiate this exciting project, but it has also provided an important platform to share this research with the Fragile X community. For me, engaging with and sharing my work with the community has been the most rewarding and impactful element of this program. I am so grateful for this experience and am honored to have been selected to participate in the Randi J. Hagerman Summer Scholars program.”
Investigation of the Potential of AZD7325 Treatment on EEG Oscillations, Gamma Waveforms, and Dendritic Spine Morphology in the Mouse Model of FXS
Supervisor: Christina Gross, PhD
Hypothesis: We hypothesize that treatment with the GABAAα2/3 agonist AZD7325 will rescue increased gamma oscillations and abnormal dendritic spine morphology in FMR1 KO mice.
Aim 1 will analyze the effect of AZD7325 treatment on basal gamma EEG power in FMR1 KO mice and their WT littermates.
Approach: We will test the potential of the GABAAα2/3 agonist, AZD7325 (AstraZeneca), on normalizing basal EEG levels and, in particular, the increased gamma EEG power observed in FMR1 KO mice. 6-8-week-old FMR1 KO mice and their WT littermates will be implanted with cortical electrodes for continuous video/EEG recording using a wireless system from Data Sciences International. Three days after surgery, baseline EEGs will be recorded for a period of 7 days to confirm basal EEG waveforms in the mice. Then, the mice will be administered with daily injections 1mg/kg of AZD7325 or the vehicle control (0.05% SBECD (Sulfobutyletherbetacyclodextrin)) in Milli-Q water for 10 consecutive days (dose established by previous studies in mice). The recorded EEG data will be analyzed for individual waveforms, total power, and relative and absolute gamma oscillations using NeuroScore software. Feasibility of these experiments is confirmed by our previous publications using mouse EEG analyses (Gross et al., 2016), and preliminary data that recapitulate published data.
Aim 2 will examine the effect of treatment of AZD7325 on dendritic spine density and morphology.
Approach: Post completion of ten days of drug treatment and recording, the mice brains will be collected and preserved for analysis of dendritic morphology. The brains will be first treated through the Golgi staining process using the FD Rapid Golgi Staining Kit as we have done previously Gross et al., 2015b. Briefly brains will be sectioned using a vibratome (160 μm slices), stained according to the manufacturer’s protocol and dendritic spines of CA1 pyramidal neurons will be imaged using a widefield microscope using a 60X objective, and quantified using Image J (NIH). The dendritic spine counting techniques are routinely performed in the laboratory (Gross et al., 2015b). Most recently, we have used a similar treatment paradigm (10 days of daily dosing) with a different drug to show that dendritic spine density was reduced after treatment. [Figures not included.]
Brain Microstates as a Window into Sensory Sensitivity in Fragile X Syndrome
Supervisor: Dr. Lauren Ethridge
This study will be the first to observe the microstates in FXS in both the resting and prestimulus states. We aim to 1) assess whether FXS, similar to ASD, maintain more stable microstates during resting EEG, and whether this is correlated with behavioral or sensory rigidity; and 2) assess whether pre-stimulus microstates affect sensory processing in FXS specifically associated with sensory hypersensitivity. We hypothesize that people with FXS will have more stable resting microstates and also will spend more time in an abnormal pre-stimulus microstate, potentially associated with increased activity in primary sensory cortices, leading to hyperexcitability and hypersensitivity to auditory stimuli.
Development and Screening of Novel Compounds for FMR1 Gene Reactivation
Affiliation: University of Wisconsin-Madison Supervisor: Dr. Xinyu Zhao, Professor of Neuroscience
Developments in stem cell research and sequence-specific synthetic molecules have presented promising opportunities for potential drug therapies of Fragile X Syndrome (FXS). FXS is an X-linked genetic disease and the largest known cause of inherited intellectual disability. Caused by a CGG repeat expansion in the FMR1 gene, FXS results in hypermethylation and subsequent shutdown of gene activity and protein expression. Past therapeutic strategies have attempted to restore FMR1 activity through drug compound screens, but to date, no compounds have successfully, fully reactivated the FMR1 gene. To address this challenge, my mentor Dr. Zhao’s lab has created a luciferase-based reporter cell line that has allowed for the large-scale screening of compounds for FMR1 gene reactivation. Additionally, my co-mentor Dr. Ansari’s lab has successfully developed sequence-specific polyamides that have been shown to bind methylated DNA and reduce methylation of targeted sites. Design of a novel polyamide compound that binds and reactivates the FMR1 gene would represent a significant step towards therapeutic strategies of FXS. Therefore, this project will focus on (1) conducting a secondary screening of potential small molecule gene reactivators and (2) aiding in the development of novel polyamide compounds that bind CGG repeats and reduce methylation of the FMR1 gene.
Social Gaze Differences in Fragile X Syndrome and Idiopathic Autism Spectrum Disorder
Supervisor: Craig Erickson, MD
There are a number of noted similar behaviors and social impairments between individuals with Fragile X syndrome and Autism spectrum disorder, so much so that roughly 30% of children with FXS also receive a diagnosis of autism. This study will investigate the fundamental differences in mechanisms that drive these behavioral features seen in both FXS and ASD, and may provide the basis to develop tools that will accurately measure social deficits specific to FXS. These findings will allow for future investigation into distinguishing features between FXS and ASD that may aid in accurate diagnosis and tailored treatment.
Ndeye Marieme Ndiaye
Social Reward Learning in Human Patients with Autism
Supervisor: Gül Dölen, MD, PhD
The recent development of a human version of the conditioned place preference (CPP) assay we use to measure the rewarding properties of social interactions in mice, dramatically improves the translational validity of neural mechanisms and therapeutic targets uncovered using this assay. Preliminary data collected in the Dölen lab indicates that FMR1 knockout autism and Fragile X model mice have impaired social reward learning. In collaboration with the Thompson lab, I will conduct experiments to test the hypothesis that patients with Fragile X and autism have a similar impairment in social reward learning, using the human version of the social CPP assay.
Genomic Editing of FMR1 Premutation in Human Fibroblast Cell Lines via Delivery of Purified Cas9 Ribonucleoproteins
Supervisor: Flora Tassone, PhD
This study will help us to better understand the impact of the CGG repeats on the different clinical premutation phenotypes and the molecular mechanisms behind the development of Fragile X-associated disorders. The CRISPR Cas9 technology has a profound impact on research efforts including identification of genes as well as the development of new disease models. The genome editing by transient expression of Cas9 (as RNP) will permit the consideration of a range of delivery options for therapeutic applications. In the future, with the optimization of suitable delivery system and proper assessment of specificity, we can clinically translate this study for the therapeutic editing in the Fragile X-associated disorders. (Also see: CRISPR, a New Genome Editing Tool: Could it Work for Fragile X-Associated Syndromes?)
Cellular and Biomolecular Characterization of Fragile X Patient Induced Pluripotent Stem Cell Derived Neurons
Affiliation: Emory University Supervisor: Dr. Gary Bassell
The loss of the Fragile X mental retardation protein (FMRP) in Fragile X syndrome has been linked to an increase in protein synthesis and increased activity of the phosphoinositide-3 kinase (PI3K) signaling pathway. Previous work in the Bassell lab has shown that FMRP directly regulates the catalytic subunit of PI3K and that reduction of overactive PI3K signaling corrects specific deficits associated with FXS. During my summer project, I used control and FXS patient-derived induced pluripotent stem cells (iPSCs) to generate neurons. Work in progress has been to characterize cellular and morphological deficits in FXS iPSC-derived neurons and assess the potential therapeutic value of PI3K inhibition.
The Effect of Genetic Background on Kv4.2 Expression in FXS Mouse Models
Affiliation: Cincinnati Children’s Medical Hospital Center Supervisor: Christina Gross, PhD
Fragile X syndrome (FXS) is often characterized by hyperactivity and is associated with epilepsy, especially in children. The underlying molecular causes of this hyperactivity remain unknown. Kv4.2, a protein that helps transmit signals between nerve cells, is a key regulator of nerve cell activity in the brain. My lab has previously shown that in a mouse model of FXS, levels of Kv4.2 are decreased. In pilot studies, which were part of my summer research, we showed similarly decreased Kv4.2 levels in another mouse model of FXS suggesting that reduced Kv4.2 function could contribute to neuronal hyperactivity and epilepsy in FXS.
My research this summer focused on regulation of Kv4.2 production, as identifying ways to increase Kv4.2 levels could potentially lead to the development of novel treatment strategies for FXS. I worked with microRNAs, which are natural and selective inhibitors of protein production that lead to reduced protein levels of their targets. I was able to confirm regulation of Kv4.2 by a specific microRNA. By inhibiting this microRNA in the future, we could potentially increase Kv4.2 expression in patients with FXS, which may help to reduce neuronal hyperactivity.
Institute A Controlled Trial of Sertraline in Young Children with Fragile X Syndrome
Affiliation: UC Davis MIND Institute Supervisor: Randi Hagerman, MD
My project involved managing the extensive process of completing a trial of sertraline in young children with FXS by bringing in the final subjects and preparing the data for analysis. The analysis is complete and we are currently writing the paper for publication. In addition, I collaborated with many brilliant people, shadowed Dr. Hagerman in patient visits, learned about the Fragile X field, and developed important research, clinical, and management skills. Ultimately, I discovered my passion for working with families affected by Fragile X and greatly look forward to specializing in FXS as a physician and researcher in the future.
Effects of Cognitive Function and Dual-Task Interference on Balance and Gait in Premutation Carriers of the Fragile X Mental Retardation 1 Gene
Affiliation:Rush University Medical Center Supervisors: Joan A. O’Keefe, PT, PhD and Deborah A. Hall, MD, PhD
My summer project was to determine the impact of cognitive interference on balance and gait function in carriers of a premutation on the Fragile X mental retardation 1 (FMR1) gene compared to age matched healthy controls. I did this using dual-task gait and balance paradigms involving i-SWAY and i-WALK inertial sensor testing in conjunction with neuropsychological assessments of executive function. My results showed no significant differences in dual-task interference between the two groups, likely due to low sample size. However, I am continuing to collect data in order to increase my sample size.
A Controlled Trial of Sertraline in Young Children with Fragile X Syndrome
Affiliation: University of California, Davis Mentor: Dr. Randy Hagerman
I had the honor of working at the UC Davis MIND Institute as a research study coordinator under the mentorship of Dr. Randi Hagerman. The study I helped coordinate looked at the benefits of a low dose of sertraline, an SSRI that increases the level of serotonin, on language, anxiety, and social deficits in young children with Fragile X syndrome (FXS).
A preliminary analysis of the first 30 subjects showed improvements in cognition, language, and social behavior through significant improvements in the CGI-I, VAS, and Mullen assessments. Working on this project has reinforced my interest in targeted treatments in FXS and I am excited to see the positive impact of this study on the younger FXS population.
This study will continue to enroll children with FXS between the ages of 24-68 months until mid-January 2015.
Excitatory/Inhibitory Modulation and the Fragile X Synapses
Affiliation: Cincinnati Children’s Hospital Medical Center Mentor: Dr. Craig A. Erickson
I worked with Drs. Craig Erickson and Tori Schaefer to assess the efficacy of two GABA(A) modulators, which boost inhibitory signaling in the FMR1 knock-out mouse model of FXS. Deficiencies in inhibitory signaling, dendritic spine number and spine morphology are suspected to contribute to the pathophysiology of FXS in both patients with FXS and in mouse models.
My work included the chronic treatment of FNR1 knock-out mice, collection and processing of brain tissue, microscopy and quantification of dendritic spine density and characterization of spine morphology.
Preliminary data indicate a differential effect of the therapeutics on the FXS dendritic spine phenotype, likely related to the different specificity of the drugs to regulate inhibitory signaling. Further studies evaluating the effects of these drugs on neural physiology and behavior are currently ongoing.
Improving Health Education for Women Who Carry an FMR1 Premutation
Affiliation: Emory University School of Medicine Mentor: Dr. Stephanie Sherman
Much of the current research on the FX premutation is focused on defining health risks (e.g. FXPOI/FXTAS) and less is dedicated to understanding the personal experiences of women seeking to understand and navigate their own health journey.
My project used focus group discussions to uncover both barriers and facilitators faced by women who carry the premutation when seeking medical care. We uncovered many barriers to personal healthcare including the lack of knowledge among medical providers, inability to keep pace with findings from research in the field, and the shortage of premutation-specific educational materials and support.
The second half of this project aims to create and distribute premutation-specific educational materials for women. Many premutation carriers face the task of educating not only themselves but also healthcare providers and family members. Having access to up-to-date materials can help diminish misperceptions regarding health risks and aid in information sharing and awareness.
Genetic Markers Predictive of Sertraline Treatment Response in Young Children with Fragile X Syndrome
Affiliation: Department of Biochemistry and Molecular Medicine, University of California, Davis Mentor: Dr. Flora Tassone
Young children with FXS can present with anxiety, irritability, and hyperactivity related to sensory hyperarousal and language delay. Recently, Winarni et al. (2012) reported that treatment with Sertraline led to improvement in expressive language capability in boys with FXS. A positive response to sertraline was recently observed (Winarni et al., 2010) in young children with FXS and autism spectrum disorders. In addition, a preliminary analysis of children in a double-blind, placebo-controlled trial of sertraline in young children with FXS showed a marked improvement in anxiety.
In this study we determined if the genetic allelic variants of several genes related to the serotonergic pathway correlate with the observed clinical response. Data analysis is currently in progress.
Winarni TI, Chonchaiya W, Adams E, Au J, Mu Y, Rivera SM, Nguyen DV, Hagerman RJ. (2012) Sertraline may improve language developmental trajectory in young children with Fragile X syndrome: a retrospective chart review. Autism ResTreat. 104317. doi: 10.1155/2012/104317.
Affiliation: Stanford University Mentor: Dr. Allan Reiss
This summer, I worked with CIBSR at Stanford University under director Dr. Allan Reiss and project manager Mai Manchanda on a double-blind, placebo-controlled trial of donepezil in Fragile X syndrome (FXS). My work included administering and scoring behavioral and cognitive outcome measures to study participants with a focus on the CNT as well as aiding with the collection of neuroimaging data, including structural and functional MRI and near infrared spectroscopy (NIRS). Furthermore, I carried out structural MRI data editing and quality checking using the brain imaging software FreeSurfer 5.3, a semi-automated anatomical parcellation and segmentation tool.
Based on preliminary analyses of CNT data, donepezil had no effect on cognition in FraX. However, our study utilized many other behavioral/cognitive outcome measures beyond the CNT that must be analyzed to further determine whether donepezil enhances cognition or behavior in FraX.
Affiliation: Emory University School of Medicine Mentor: Peng Jin
Given the high prevalence of Fragile X premutation carriers among the general population and the high risk of developing FXTAS among the male carriers, it is important to develop therapeutic intervention for FXTAS. Using our established assay, we screened multiple libraries, and identified and validated 34 small molecules. Some of them have the unknown biological activities while others have been implicated in different biological pathways, which will be further tested in the mammalian system in the near future. Our studies should provide new insight on the therapeutic development for FXTAS.
Fragile X syndrome is characterized by hyperactivity, and about 25% of patients have epilepsy. FMRP, the protein lost in Fragile X, regulates many different functions in nerve cells. One of its targets is Kv4.2, a protein that is critical for the activity of brain cells. Abnormal levels of Kv4.2 in FXS patients may contribute to the cause of epilepsy. My project was to determine how Kv4.2 is regulated by FMRP. The results suggest a new model for the regulation of Kv4.2 by FMRP.