Neuroscience

Trajectories and markers of neurodegeneration in fragile X premutation carriers

Description:
This project is a longitudinal study to examine changes in brain structure, function, and neuropsychological factors in men with the fragile X premutation who are at risk for neurodegenerative disease in the form of fragile X associated tremor ataxia syndrome (FXTAS).

Funding:
National Institute of Neurological Disorders and Stroke

A cognitive test battery for intellectual disabilities

Description:
The aim of this project is to develop and validate a cognitive battery for intellectual disabilities so that investigators will have a sensitive and developmentally appropriate set of tools for tracking improvement in key domains such as attention, memory, and processing speed in the context of clinical trials.

Funding:
National Institute of Neurological Disorders and Stroke

Genotype-phenotype relationships in fragile X families

Description:
This study of individuals with fragile X associated tremor ataxia syndrome (FXTAS) will quantify (with clinical, radiological, and molecular/bioenergetic measures) our understanding of progression, elucidate those co-morbid conditions that modulate progression,and identify the most informative biomarkers of severity and progression.

Funding:
National Institute of Child Health and Human Development

FAST research infrastructure grant: Training the next generation of Angelman Syndrome scientists

The goal of this project is to create a stable infrastructure for the rapid testing of potential therapeutics in rodent models of Angelman syndrome (AS). Two important sub-projects are described:

The first is the investigation of the protein phosphatase 2A inhibitor LB-100, which was recently reported to rescue deficits in motor function and learning in a mouse model of AS. This project will seek to independently validate the reported observations in the mouse model and, if successful, further characterize the effects of LB-100 use more translationally relevant assays in the rat model. Molecular and electrophysiological analyses will also seek to validate reported improvements in spine maturation and synaptic transmission.

The second example project is a medium-throughput screening project of a small drug library in reporter neurons. Hits from the screening effort will advance to subsequent mouse studies as in the first project.

Funding:
Foundation for Angelman Syndrome for Therapeutics (FAST)

Targeted therapeutic development program for SYNGAP1-related intellectual disability

The goals of the research program are: (1) the development of an innovative therapeutic agent targeting direct rescue of SYNGAP1 expression that is not an antisense oligonucleotide in mechanism and (2) the assessment of the efficacy of therapeutic agent(s) in well-characterized cell, rodent, and models of the disorder as well as a novel model.

Funding:
RDM Positive Impact Foundation

Phenotypic characterization of novel models of Dup15q Syndrome

Duplications or triplications of the chromosomal region 15q11.2-q13 (Dup15q) are one of the most common genetic causes of autism and intellectual disability. The ubiquitin E3A ligase gene (UBE3A) located within the 15q11.2-q13 region is parentally imprinted and expressed only from the maternal allele in most neurons. Three differentially spliced isoforms of UBE3A have been identified; however, it is not known which isoform plays the most critical role in Dup15q. Since UBE3A is imprinted specifically in neurons, this project will test the hypothesis that elevated UBE3A in neurons is the major contributor to Dup15q phenotypes. We will further assess to the contribution of each isoform of Ube3a, by characterizing functional outcomes, neuropathology, and epigenetic marks in transgenic mice with neuronal forebrain overexpression of Ube3a Isoform 1, 2, and 3.

Funding:
National Institutes of Health / National Institute of Neurological Disorders and Stroke

Chromatin remodeling factor dosage-sensitivity in neurodevelopmental disorders

This study aims to characterize the effects of CHD8 mutations on brain development and neuronal function. CHD8 is a chromatin remodeling gene with the highest rate of mutations associated with neurodevelopmental disorders (NDD) and autism spectrum disorders (ASD). The specific focus is on the impact of Chd8 haploinsufficiency on chromatin remodeling, transcription, and neurogenesis during brain development.

The potential significance is high as the study may provide novel insights into Chd8 function and how the haploinsufficiency of Chd8 contributes to NDD and ASD.

Funding:
National Institutes of Health

Translational analysis of gait as a primary outcome measure in Angelman Syndrome

Movement disorders affect nearly every individual with Angelman Syndrome (AS). This study is a one-of-a-kind multifaceted, collaborative project to identify outcomes measures relevant to individuals with AS, but also using Ube3a mutant rodent models, so we have truly translational / identical outcome measures to test therapeutics and expedite clinical trial processing through the FDA. By increasing the number of relevant, innovative, in vivo functional outcome measures, we will create more opportunities for identifying and moving forward successful medical interventions.

Funding:
Foundation for Angelman Syndrome for Therapeutics (FAST)

Assessment of antisense oligonucleotides for Dup15q Syndrome

The goals of this program of research are to find optimal dose of two differing antisense oligonucleotides for Dup15q Syndrome, to confirm in vivo target engagement and to assess efficacy.

Funding:
Ultragenyx Pharmaceutical

Automated measurement of language outcomes for neurodevelopmental disorders

Description:
This project is focused on evaluating whether computational natural language processing methods can be translated into meaningful outcome measures for individuals with neurodevelopmental disorders including, Down syndrome, fragile X syndrome, autism spectrum disorder, and attention deficit/hyperactivity disorder. The aims are to: (1) identify pivotal parameter settings that optimize stability of automated discourse measures generated from naturalistic language samples (NLS) and examine responsiveness to real change; (2) evaluate the consistency of these NLS automated discourse measures and identify key measurement factors that impact consistency; and (3) evaluate the validity of these automated discourse measures and differences in validity as a function of diagnostic group, IQ, and language ability.

Funding:
National Institutes Health

Early communication outcome measures for Down syndrome

Description:
This project brings together collaborating teams at UCDavis MIND Institute, Colorado State University, Cincinnati Children’s Hospital Medical Center, and the University of Louisville to evaluate the feasibility and psychometric properties of a variety of prelinguistic and spoken language metrics collected in naturalistic contexts for use in treatment studies focused on young children with Down syndrome (DS).

The aims are to (1) evaluate the psychometrics of four metrics of early communication development, (2) evaluate the psychometrics of four metrics of spoken language ability, and (3) characterize the developmental trajectories of these various prelinguistic and spoken language metrics in young children with DS through cross-sectional approaches.

Funding:
National Institutes of Health / National Institute on Deafness and Other Communication Disorders

Language development and fragile X syndrome in males and females

Description:
The proposed project extends previously funded, Language Development in fragile X syndrome (FXS). We will continue the longitudinal investigation of males with FXS into adulthood and begin tracking the trajectories of females with FXS, who have been understudied, especially in the adult years.

The aims are to (1) describe the development of language, literacy, and the capacity for independent functioning in FXS during the transition into adulthood; (2) evaluate for the first time the bidirectional relationships between the capacity for independent functioning and language and literacy; (3) identify the determinants of within-syndrome variation in language literacy; and (4) identify sex differences in language, literacy, and the capacity for independent functioning.

Funding:
National Institutes Health

Memory measures for clinical trials in Down syndrome and fragile X

Description:
Because a number of proposed pharmacological agents target the function of the hippocampus, memory will likely be designated as a “primary” outcome in a number of upcoming trials. This makes memory test validation a critical next step in supporting pharmacological approaches to cognitive interventions in intellectual disability (ID). In this revision, we plan to further develop and validate a theoretically-informed, comprehensive android touch-screen memory assessment system for use in young children with ID by considering the effects of sleep on the proposed memory outcome measures in individuals with Down syndrome, fragile X syndrome, and in two samples of typically developing children matched on either mental-age or chronological-age.

Funding:
National Institutes Health