Faculty Advisor

Mark Alkema

Faculty Advisor

David S. Adams

Faculty Advisor

Kwonmoo Lee

Faculty Advisor

Dirk Albrecht

Faculty Advisor

George D. Pins

Identifier

etd-042618-170026

Abstract

Nearly one billion people worldwide have a neurological disease, and one out of every six adults in the United States has a mental illness. For rare and severe neurodevelopmental disorders, like Timothy syndrome (TS), exact genetic causes have been identified and studied extensively. TS is caused by a single point mutation in CACNA1C, a voltage-gated calcium channel (VGCC), which results in severe developmental defects, cardiac arrhythmia, and autism. Studies using patient derived cells are useful in identifying impaired cellular function, especially for TS and other neural activity-dependent disorders. Also, functional high-throughput screening assays that use disease-relevant cell types can lead to more targeted therapeutics that regulate cellular activity. Although these approaches are promising, cell-based assays do not consider the diversity of disease pathology or efficacy of broad-acting therapeutics in multi-cellular organisms. Therefore, we developed several whole-organism disease models using CRISPR-Cas9 and transgenes in the nematode C. elegans that harbor human VGCC mutations. We evaluated and identified behavioral, morphological, and functional phenotypes, and invented new high-throughput functional screening technologies to identify transient and potent suppressors of neural activity in these animals. We expect that these new disease models and methods will provide a pipeline for investigating activity- dependent neurological disorders in whole organisms to identify more effective therapeutics. Altogether, we aim to deepen our understanding about the brain and discover treatments for the millions of individuals that suffer from neurological disease.

Publisher

Worcester Polytechnic Institute

Degree Name

PhD

Department

Biomedical Engineering

Project Type

Dissertation

Date Accepted

2018-04-26

Accessibility

Restricted-WPI community only

Subjects

Biomedical engineering, C. elegans, Neuroscience, Neurological disease, Assay systems

Available for download on Monday, April 29, 2019

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