SFARI | Search Results for “ben-ari”

A human stem cell-based neuronal network platform for functional validation of autism-linked variants

In the current project, Nael Nadif Kasri aims to establish an all-human iPSC-based neuronal network platform to rigorously and multiparametrically assess the consequences of specific mutations in ASD risk genes on neuronal network function. The platform will be used to assess selected ASD gene variants of unknown significance and as a first-tier in vitro selection platform for testing genetic strategies for the amelioration of neuropathological phenotypes associated with genetically defined ASDs.

Functionalizing the autism variome

The list of risk genes for ASD with associated mutations continues to grow at a substantial pace, but for many of these mutations, a basic understanding of the functional impact of the mutations on the encoded proteins is missing. In this project, Marc Vidal and Lilia Iakoucheva plan to functionally characterize a collection of ASD gene variants by assessing the effects of mutations on protein stability and protein-protein interactions. This integrative approach will enable the identification of causative variants and characterization of the functional impact of these variants in the context of brain-expressed isoforms.

Assessing mRNA translation dysregulation in Gigyf1/2 mouse models of autism

The SFARI gene database lists both GIGYF1 and GIGYF2 as high confidence risk factors, as both have a probability of loss of function intolerance (pLI) score of 1. It is our hypothesis that GIGYF1/2 mutations disrupt the function of the GIGYF1/2-4EHP translation repression, thus resulting in dysregulation of protein synthesis which causes impaired synaptic function and susceptibility to behavioral impairments. We will use cell-specific GIGYF1/2 conditional knockout mice, which will be subjected to a battery of behavioral tests, ribosome profiling and proteomics to investigate the mice for behavioral impairments and changes in translational efficiency. Our goal is to provide novel insight into the molecular mechanisms mediating ASD-like behaviors via GIGYF1/2 and establish a preclinical basis for therapeutic intervention in ASD patients.

Circuit mechanisms mediating social attachment deficits in ASD

Linking ASD risk genes to sensorimotor circuits for dynamic social communication

Neural correlates of sensory hypersensitivity in autism spectrum disorder

Most individuals with autism experience at least one form of hypersensitivity from the five senses. These alterations in sensory-related behaviors can lead to profound limitations on an individual’s ability to work, interact with family and participate in leisure activities. Furthermore, these atypical responses to otherwise normal sensory stimuli may be closely associated with the core symptoms of autism, such as social deficits and repetitive behaviors. Despite the importance of sensory abnormalities in the pathogenesis of autism, how the brains of individuals with autism receive information from the five senses at the subcortical level and how such information becomes transformed into aversive responses has not been investigated.

Identifying convergent cortical circuit impairments across multiple mouse models of autism

Jess Cardin and Michael J. Higley will establish a functional screen (using a CRISPR/Cas9-induced gene disruption system and multiscale in vivo calcium imaging in awake mice) for the assessment of common cellular- and circuit-level cortical dysregulation phenotypes associated with mutations in ASD risk genes.

Using newly developed computational tools to assess the contribution of tandem repeat mutations to autism risk

De novo mutations contribute to a large fraction of autism spectrum disorders (ASD) risk, but the contribution of complex variant types remains largely unexplored. Melissa Gymrek aims to utilize her recently developed novel computational tools to evaluate the role of genetic variation in repetitive regions of the genome in ASD.

The neuroscience and genetic basis of twice exceptionality: A pilot study

Individuals who have very high cognitive and intellectual ability coupled with a diagnosis of autism are known as twice exceptional (2e). In partnership with the SFARI-funded SPARK initiative, Jacob Michaelson will recruit a cohort of 2e individuals with autism and collect genetic and neuroimaging data on these individuals in order to better understand the neurobiology of this underserved population.

Investigating social communication and attachment deficits in prairie vole models of autism

The sensory and neural mechanisms that mediate social communication facilitating attachment and how they are affected in the context of autism spectrum disorder (ASD) are poorly understood. Prairie voles are small rodents that display long-term relationships between peers and mates. Devanand Manoli proposes to understand how specific mutations in two ASD risk genes, Shank3 and Scn2a, disrupt the processing of social cues, leading to the identification of brain regions that could inform targeted interventions to improve social communication in ASD.