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Molecular, Cellular and Behavioral Characterization of Prenatal Treatment Effects in Mouse Models of Down Syndrome

National Human Genome Research Institute , Bethesda, MD and surrounding area

Position Description:
Down syndrome (DS) is the most common genetic cause of intellectual disability, affecting 1:700 newborns. In prior work, we used an integrated and lifespan approach based on gene expression data from multiple human cell types/tissues and fetal brain from three different mouse models of DS (Dp16, Ts65Dn and Ts1Cje) to identify consistently dysregulated signaling pathways and cellular processes. These included cell cycle defects, inflammation, oxidative stress and mitochondrial dysfunction, among others. We also used the Connectivity Map (CMap) database (https://www.broadinstitute.org/connectivity-map-cmap) to identify FDA-approved molecules that are predicted to counteract these pathway abnormalities and can be tested in vitro and in vivo (mouse models of DS) (Guedj et al, 2016 PMID 27586445). We identified 17 molecules predicted to rescue transcriptome changes in both humans and mice with DS. We are currently testing the safety and efficacy of these drug candidates in the Dp16, T65Dn and Ts1Cje mouse models.

This project will provide preclinical safety and efficacy data regarding treatment in the three best-known mouse models of DS, and if successful, will eventually allow us to start a human clinical trial to determine if prenatal treatment of DS has beneficial effects on cognition. This project has two main aims:

Aim I: Identify reliable molecular, cellular and behavioral endpoints in the Dp16, Ts65Dn and Ts1Cje models that have human clinical correlation across the lifespan and that can be used to analyze the effects of treatment.

Aim II: Investigate the short and long-term effects of prenatal versus postnatal treatment with objectively selected small molecules that can rescue phenotypic deficits in DS.

Qualifications:
We are looking for an independent and highly motivated postdoctoral fellow within his two first years of PhD graduation, and who is interested in pursuing a career in translational neurogenetics. The ideal candidate will work with an interdisciplinary team working together and using in vitro and in vivo approaches to develop effective prenatal therapeutic interventions for DS. The ideal candidate will be responsible of characterizing molecular, cellular and behavioral phenotypic deficits in three different mouse models of DS. He will also be responsible of investigating the effects of prenatal treatment with candidate molecules selected for safety and efficacy in human amniocytes and neural stem cells from individuals with DS.

The ideal candidate should have expertise in:
1) Mouse behavioral testing: Using SHIRPA screen, open field, rotarod, contextual fear conditioning and Morris water maze to analyze exploratory behavior, motor coordination and learning/memory.

2) Touch screen behavioral testing: Using Lafayette mouse modular chambers to analyze human translational cognitive outcomes using the Cambridge Neuropsychological Test Automated Battery (CANTAB), including the visual discrimination, reversal, PAL, extinction, 5-CSRT and TUNL.

3) Live animal recording: Field recording in the cortex and hippocampus to investigate the effect of the treatment during behavioral testing.

4) Imaging and stereology: Brain sectioning (embryonic, neonatal and adult), immunohistochemistry staining with different markers of CNS cell populations and cell counting in different brain regions as well as neuronal and spines reconstruction using IMARIS.

5) Mechanistic/molecular approaches: Transcriptomics and proteomics to analyze the pathway dysregulations and the effects of the treatment using microarrays, QPCR, Western blotting...

Additional skills include:

  • Being able to independently design experiments, setup research objectives and show progress on a timely fashion.• Maintaining and updating experimental data in laboratory notebooks and drives.
  • Collecting, organizing and analyzing data from the daily experiments.
  • Attending weekly laboratory meetings and presents findings to rest of the team.
  • Attending educational lectures organized at NIH as appropriate for research project.
  • Submitting abstracts for international conferences and writing research progress reports and manuscripts.

To Apply:
Applications should include a detailed resume, a personal statement describing the candidate research interest and career goals and a minimum of two recommendation letters from former mentors. *PLEASE NOTE: The selection and hiring process must be completed by the end of September 2017; as a result, it is only possible for current US Citizens or resident aliens to apply to the active listing and be eligible to be hired in this time frame.*

Applications should be sent to:

Dr. Diana Bianchi
Diana.bianchi@nih.gov

Dr. Faycal Guedj
Faycal.guedj@nih.gov

After selection of his/her application, the candidate will go through two rounds of interviews:
1) First, a phone or conference call interview.
2) A formal visit to the National Institutes of Health and the Bianchi lab. During the second interview, the candidate will present their previous research and research objectives during his/her training in the Bianchi Lab. He/She will also meet the Bianchi Lab members and the different core facilities and labs at the Medical Genetics Branch of the NIH.

The NIH is dedicated to building a diverse community in its training and employment programs.