My lab studies the genetic factors and molecular mechanisms underlying age-related neurodegenarative diseases, with a focus on Alzheimer’s (AD) and Parkinson’s (PD) diseases and other conditions in this spectrum.
A genomic-wide association study (GWAS) discovered an extensive list of genomic loci associated with neurodegenerative disease risk. However, the causal genetic variants, their functional effects and the underpinning biological pathways remain largely unknown. Dr. Chiba-Falek's research goal is to identify the precise causal and functional genetic variants underlying the reported associations, and understand their molecular mechanisms of action and the biological pathways through which they exert their pathogenic effects.
Single nucleotide polymorphisms (SNPs) have taken the spotlight in GWA studies of complex diseases including late-onset neurodegenerative diseases and expression traits (eQTL), but the actual functional/regulatory variants have not yet been identified. Broad classes of Structural Variants (SVs), such as short tandem repeats (STRs), homopolymers and indels, were underrepresented, mainly due to GWAS platforms that enabled high density SNP genotyping, and the difficulties to accurately read long contiguous repetitive sequences using most of the current next-generation sequencing (NGS) technologies. Genetic variability in noncoding regions is likely to affect gene regulation and may alter biological function. It has been suggested that SVs have regulatory functions in gene transcription and splicing that underscore the possible roles of noncoding SVs in the etiology of human complex diseases.
Researchers in the Chiba-Falek Lab are particularly interested in the functional consequence of noncoding (intronic, UTRs and intergenic regions) SVs and their impact on mRNA expression and splicing, and neurodegenerative-related phenotypes. Their central hypothesis is that changes in expression regulation of specific genes disrupt their related biological pathways, and can contribute to the pathogenesis of neurodegenerative diseases, and the expression levels of these genes are regulated, at least in part, by noncoding SVs and hence suggest the molecular mechanism underlying the reported genetic associations with disease-risk. To test the hypothesis they are conducting investigations using three model loci that represent different categories of small-scale SVs:
(1) A highly variable intronic poly-T site in the TOMM40 gene in relation to late onset AD (LOAD) and cognitive decline in normal aging.
(2) A highly polymorphic, complex microsatellite located ~10kb upstream of the SNCA gene in the context of PD-risk.
(3) A highly-polymorphic-low-complexity CT-rich region resides in a large (~90kb) intron of SNCA gene that consists of a cluster of SVs including repetitive sequences and indels, and its role in comorbidity of Lewy body pathology in AD patients (LBV/AD).
The Chiba-Falek Lab research program involved state-of-the-art technologies including, novel bioinformatics tools to annotate and prioritize SVs, phased sequencing, Laser Capture Microdissection (LCM), NanoString nCounter Single Cell gene expression, and genome editing (CRISPR/Cas9); and a variety of model-system approaches such as, disease-affected and normal human brain tissues, luciferase reporter system, humanized mouse model, and iPSCs.
Ornit Chiba-Falek received her Ph.D. from Hebrew University in 1999. She is an Associate Professor of Neurology and has been awarded research grants by National Institutes of Health (NIH).