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Language
English
Title and Department
Associate Professor
Department of Medicine, Division of Genetic Medicine
Associate Professor
Department of Cell and Developmental Biology
Professional bio

Ela W. Knapik, MD, is a Professor in the Division of Genetic Medicine within the Department of Medicine at Vanderbilt University Medical Center. Her lab is focused on understanding mechanisms of protein transport and secretion through modeling of human diseases.

The Knapik laboratory uses in vivo approaches in zebrafish (Danio rerio) to model and manipulate the genetic and developmental processes that underlie the pathophysiology of human disease. Lab members use genetic mutations induced by CRISPR/Cas9 genome editing or chemically-induced random variants to assess disease phenotypes, gene function, and pathway interactions. In parallel with the zebrafish models of human diseases, lab members also use mammalian cell culture and biochemical approaches.

Researchers in the Knapik Lab have focused our research on three main areas:

(i) The mechanisms and pathways directing extracellular matrix traffic and deposition
(ii) The pathophysiology of diseases, including developmental and neuropsychiatric disorders
(iii) Modeling of human variants for drug development and testing

Here are further details on these three research fronts:

(i) Disruptions in the synthesis, processing or secretion of extracellular matrix (ECM) macromolecules are associated with human diseases, including osteogenesis imperfecta (OI), multiple epiphyseal dysplasia, cranio-lenticulo-sutural dysplasia, and congenital disorders of glycosylation (CDG). Our laboratory has successfully modeled these human diseases in zebrafish and contributed to understanding basic developmental mechanisms and cellular pathways that direct ECM traffic and deposition. Using phenotype-driven forward genetic screens and positional cloning, we have identified point mutations responsible for skeletal malformations in zebrafish, and currently, we are working to show how defects in the secretory pathway affect skeletal biology, chondrocyte cell shape and ECM deposition.

(ii) Additionally, we are modeling Mendelian disorders such as chylomicron retention disease and zinc transporter deficits, as well as comorbidities associated with complex neuropsychiatric diseases (ASD, MDD, SCZ, BD, ADHD, OCD) such as skeletal dysmorphology, seizures and gastrointestinal disturbances. In collaboration with the Vanderbilt Genetics Institute (VGI) investigators, we examine effects of genetic variation, identified by statistical genetic methods in BioVU, on gene function and resulting phenotypic spectrum. Using CRISPR/Cas9 genome editing, we are generating zebrafish knockout and transgenic lines that are evaluated by in vivo and ex vivo methods for discovery of primary genetic mechanisms underlying the pathophysiology of these diseases.

(iii) Zebrafish is ideally suited for modeling of human single nucleotide polymorphisms (SNPs) in genes identified through BioVU variant investigations. We can test whether a specific SNP increases or decreases gene activity, thus altering protein function, such as receptor activity, for example. These models are particularly helpful in testing responses to known pharmacological agents and in drug screens for new pharmaceuticals. We are using CRISPR/Cas9–based knockout and knockin strategies in stable zebrafish lines that are then evaluated for phenotype and gene function. This early functional genomics assessment model offers rapid and powerful tool in the drug discovery pipeline.