Current Projects

Chronic Traumatic Encepthalopathy and the Pan-Neurodegenerative Disease Phenotype

Current as of 7/5/2018

PI: Adam Labadorf
Hub Analyst: Ikjot Sidhu

An increasing body of research suggests that multiple neurodegenerative diseases (NDs) share common aspects of pathology and response in human brain. In particular, genes related to neuroinflammation and neuroimmune response have recently been shown to be consistently altered in the post mortem brains of both Huntington's and Parkinson's disease subjects.Chronic Traumatic Encephalopathy (CTE) is increasingly recognized as a ND associated with repetitive acute traumatic brain injury, and brains obtained from individuals with CTE have a higher prevalence of other NDs, including parkinsonism (Lewy bodies) and Alzheimer's Disease. We hypothesize that there is a common set of neuroinflammatory pathways invoked by neurodegeneration across HD, PD, and CTE that is detectable by genome-wide transcriptional analysis measured by high throughput mRNA sequencing (mRNA-Seq). In this study, we will identify the transcriptional signature in human post mortem brain from individuals with CTE as part of our larger effort to understand the holistic response of the brain to neurodegeneration.

Genetic Risk Factors in Chronic Traumatic Encephalopathy

Current as of 7/5/2018

PI: Thor Stein
Hub Analyst: Nate Bourgeois

Repetitive head impacts (RHI) are a form of mild traumatic brain injury that can lead to severe cognitive and behavioral symptoms and the progressive neurodegeneration of chronic traumatic encephalopathy (CTE). Trauma is also a known risk factor for Alzheimer disease (AD), and we hypothesize that a prolonged period of RHI can play a causative role in the development of AD as well as CTE. We hypothesize that the AD genetic risk variants APOE and TMEM106B are enriched in CTE and CTE-AD subjects and are associated with altered cytokines and increased levels of beta-amyloid and tau and progression of disease. We further hypothesize that genomic variation in known AD genes will predict risk or progression of CTE and CTE-AD following RHI exposure and that levels of beta-amyloid, tau, and neuroinflammatory cytokines may serve as biomarkers for trauma-induced neurodegeneration. In this project, we analyze the genome-wide transcriptional profile of brains from individuals who died with a range of CTE pathology to identify associations of gene expression with these AD risk variants and histological measurements of neurodegeneration.

microRNA sequencing data in Parkinson's Disease

Current as of 1/4/2017

PI: Rick Myers
Hub Analyst: Ryan Ingram

This project involves the study of micro-RNAs (miRNAs) using high throughput sequencing (miRNASeq) data generated from the cerebrospinal fluid (CSF) and brains of post-mortem Parkinson's Disease (PD) patients. Previous studies have shown a distinct signature of miRNA expression in the brain is associated with PD patients compared with neurologically normal controls. miRNA-Seq datasets using CSF samples from the same individuals were also generated in a separate study. The goal of this study is to determine if the signature discovered in brains can be detected in the CSF from the same individuals. A state of the art miRNA-Seq analysis pipeline is used to process the datasets and advanced statistical techniques using Firth's logistic regression, cross validation, and bootstrapping are employed to identify miRNAs that are consistently perturbed in PD compared with control tissues.

mRNA-Seq analysis of affected brain regions in manifest and asymptomatic Huntington’s Disease

Current as of 1/4/2017

PI: Rick Myers
Hub Analysts: Felisia Agus and Diego Crespo

Very little is known about the disease process in the asymptomatic Huntington's Disease (HD) brain, in large part due to the limited availability of post-mortem tissues from individuals with HD. The primarily affected region in the HD brain is the striatum, which is massively degenerated in late-stage HD and difficult to study. However, the prefrontal cortex is relatively unaffected. The Myers lab has generated mRNA-Seq data from post-mortem BA9 of 29 individuals with HD, including two asymptomatic individuals, and 49 neurologically normal controls. Nine of the HD samples have not been previously studied or published. For the two asymptomatic individuals, mRNA was sequenced from striatal tissues as well, creating the exciting opportunity to compare the molecular signature of these two brain regions within the same individuals. Identifying which transcriptional changes in the cortex correlate with those in the striatum may lead to a better understanding of the active, as opposed to reactive, disease processes, and help to better interpret the signals observed in the brains of symptomatic HD brains.

Topologically Associated Domain (TAD) Analysis in Post-Mortem Huntington's Disease mRNA-Seq

Current as of 6/12/2017

Internal Hub Project
Hub Analyst: Eve Byington

mRNA-Seq analysis of GPS2 KO vs WT murine adipocytes

Current as of 1/11/2017

PI: Valentina Perissi
Hub Analyst: Joey Orofino (grad student in the Perissi lab)

GPS2 is a small multifunctional protein with known functions in mediating inflammation and lipid metabolism. GPS2 adipose specific knockout mice (GPS2-AKO) display improved systemic insulin sensitivity and lipid storage capacity despite becoming obese. This project aims to characterize the mRNA expression of mature adipocytes from GPS2-AKO mice and explore how changes in gene expression may contribute to this phenotype. High throughput mRNA-Seq datasets were generated using adipocytes isolated from four GPS-AKO and four WT mice and analyzed using a state of the art mRNA-seq pipeline to identify a gene expression signature associated with GPS2 KO.

ALT+ vs ALT- Osteosarcoma Cell Line and Patient Derived Xenograph Gene Expression Signature by mRNA-Seq

Current as of 6/12/2017

PI: Rachel Flynn
Hub Analyst: Anqi (Angel) Dai

Telomere elongation is a requisite for cellular immortality and a hallmark of cancer cells. The majority of cancer cells rely on reactivation of the enzyme telomerase or activation of the Alternative Lengthening of Telomeres pathway (ALT) to promote telomere elongation. ALT promotes telomere elongation by using another telomeric sequence as a template for homology directed DNA damage repair. The ALT mechanism is active in 10-15% of all human cancers, but is seen in as many as 60% of tumors for the most aggressive forms of human cancer, including osteosarcoma and glioblastoma. The Flynn Lab has in its possession the most comprehensive set of ALT positive (ALT+) and ALT negative (ALT-) osteosarcoma cell lines available. Analysis of publicly available microarray datasets of osteosarcoma cell lines suggests a gene expression signature exists that can discriminate between ALT + and ALT – cell types. However, given that these data sets were generated by several different labs for different studies, they contain many uncontrolled variables limiting the utility of this analysis. This study seeks to identify a gene expression signature using the ALT+ and ALT- cell lines using high throughput mRNA sequencing. We will then use this signature to determine ALT status in primary osteosarcoma tumor samples. A secondary objective will be to use the differentially expressed genes identified by sequencing analysis to determine putative molecular mechanisms underlying the ALT+ phenotype.

Past Projects

Measuring the epitranscriptome via engineered RNA POL I and RNASeq in humans and zebrafish

PI: Daniel Cifuentes
Completed 2/2017

Epi-transcriptome m6A Detection by 2OMe-Seq in Zebrafish Development

PI: Daniel Cifuentes
Hub Analyst: Kylie Shen
Completed 8/2017

Microbial RNA-Seq analysis of variable complement-binding streptococcus pneumoniae

Current as of 1/31/2017

Streptococcus pneumoniae is a Gram-positive bacterium that is a common cause of pneumonia, particularly in children and the elderly. The genomes of dozens of SP strains from around the world have been isolated and sequenced, revealing substantial genetic diversity outside of a common set of genes that comprises about 70% of the genome. Recently, two clinically isolated strains of SP have shown variable binding and activation of the C3 complement complex in the immune systems of chinchillas, where some strains induce a stronger immune response associated with better prognosis than others. Neither the genotype nor conventional capsule markers distinguish between these strains, suggesting a transcriptional role might be useful in predicting complement binding status. The Schnyder lab has generated whole-transcriptome deep RNA-Seq datasets for six clinical isolates, three with high-C3 and three with low-C3 binding activity, to identify potential RNA elements associated with binding status. The genomes of these isolates have also been fully sequenced. Cutting edge, custom bioinformatics algorithms are applied to identify differential expression on a synteny- and gene-centric basis.