Single Cell Transcriptomics

Deciphering gene dysregulation in the immune system in ME/CFS

Despite our lack of understanding of ME/CFS, substantial evidence implicates immune dysregulation either as an underlying cause or major consequence of the disease. Nevertheless, the identity of specific dysregulated leukocytes (white blood cells, WBC) that are most implicated in ME/CFS is unclear. We propose to elucidate immune dysregulation in ME/CFS by comprehensively investigating gene regulation defects in patients across all types of leukocytes.

We will use single-cell RNA sequencing (scRNAseq) to interrogate the transcriptomes of leukocytes from peripheral blood collected from a cohort of ME/CFS patients and controls. This novel approach offers multiple advantages over all previous gene regulatory studies of the disease. We will be able to discover coordinate changes in gene regulation between different cell types.

We will extend our use of scRNAseq to compare leukocyte profiles from patients and controls post-exercise. These experiments are motivated by the need to better understand aberrant gene regulation in specific leukocytes resulting from exercise in ME/CFS patients,
as post-exertional malaise is a defining symptom of the disease.

We will examine possible roles for microRNAs found in extracellular vesicles in ME/CFS. Extracellular vesicles are a newly discovered class of particles secreted by donor cells, which deliver cargoes, including miRNAs, to recipient cells, thereby altering the state of the recipient cell. We will test the hypothesis that miRNAs in EVs are altered in ME/CFS, examining samples obtained pre- and post- exercise challenge, and examine whether such alterations result in dysregulation of patient immune cells.

The unifying theme of this study is to provide definitive data on gene regulatory changes in leukocytes from ME/CFS patients and investigate whether microRNAs in EVs contribute to such changes.

This project will be led by Dr. Andrew Grimson at Cornell University, whose lab specializes in genomics of gene regulation. He has had extensive experience in eukaryotic RNA biology, including small RNA biology. Dr. Fabien Campagne, Associate Director of the Biomedical Informatics Core at Weill Cornell Medicine, will assist with the design of reproducible single cell gene expression data aanlsysis pipelines and develop biomarker models for ME/CFS and the effect of exercise on gene dysregulation. Dr. Avery August, Professor of Immunology in Verterinary Medicine at Cornell will assist with data interpretation and purification and evaluation of immune cells.

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