2018 NFXF Summer Scholar Research Awards

//2018 NFXF Summer Scholar Research Awards

2018 NFXF Summer Scholar Research Awards

Each year, the National Fragile X Foundation funds one or more summer student research fellowships at $2500 each through the Summer Student Fellowship Research Fund. The student’s work can be in the area of Fragile X syndrome (FXS), Fragile X-associated tremor/ataxia syndrome (FXTAS), or Fragile X-associated primary ovarian insufficiency (FXPOI). This award is meant to introduce undergraduate students, or students in professional training programs, to research in the Fragile X field, by providing funding for a summer project. We understand the importance of investing in the future of Fragile X, and this award is part of our commitment to fostering the researchers of tomorrow.

Below are this year’s recipients, along with their project titles. In the fall, we will report back with summaries of their findings:

 

Investigation of the potential of AZD7325 treatment on EEG oscillations, gamma waveforms, and dendritic spine morphology in the mouse model of FXS

Andrew Snider

Supervisor: Christina Gross, PhD

Aims and Hypothesis

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 (Fig. 1).

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.    [JDW note – I did not include the Figures here]

 

Brain Microstates as a Window into Sensory Sensitivity in Fragile X Syndrome

By Kara Brown

Supervisor: Dr. Lauren Ethridge

Aims and Hypothesis

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

By Ryan Risgaard

Supervisor: Dr. Xinyu Zhao, Professor of Neuroscience, University of Wisconsin-Madison

Aims and Hypothesis

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.

By | 2018-05-14T16:09:17+00:00 May 14, 2018|Research|Comments Off on 2018 NFXF Summer Scholar Research Awards