Cellular Phenotyping of Endometriosis? Toward Biomarker Discovery and a Mechanistic Understanding of Disease
Abstract
Rationale: Endometriosis is a common gynecological disorder that results when tissue that normally lines the inside of a woman’s uterus — the endometrium — grows outside the uterus. The tissue forms large lesions that most typically implant in the ovaries, fallopian tubes, and the tissue lining the pelvis, causing severe and debilitating pain, fatigue, and infertility. The condition can only be diagnosed through surgical removal of lesions, and treatment is aimed primarily at managing the pain symptoms. Removal of endometriosis lesions offers temporary relief, but lesions and their associated symptoms frequently recur in patients. There is no cure. Endometriosis is a significant health and economic burden owing to disability and lost productivity among women. This is a particular challenge among women in the military, who may be unable to perform their military duties when symptoms are severe. As a result, endometriosis is considered a disqualifying condition for active service, thereby preventing many women who may wish to serve their country from doing so. A major reason why we lack options for diagnosing and treating endometriosis is because our understanding of the fundamental mechanisms of disease remains poor. It is known that genetic background and environmental factors play a role, but how these combine to create the conditions for endometriosis to develop is unknown. More recent studies have focused on identifying which genes are expressed in lesions as a way to identify potential disease mechanisms, but these studies have looked at the whole lesion, rather than individual cell types. Lesions are complex tissues that comprise many different cell types, each of which express unique sets of genes that may differentially contribute to disease etiology. Furthermore, few if any studies have considered the role of the local lesion environment, which may contain molecular factors that foster the development of lesions. Understanding the cell types and cell-type-specific gene expression patterns in the lesion and the surrounding environment is a foundational step that will inform hypotheses on the etiology and pathogenesis of disease and reveal the molecular factors that could represent viable targets for diagnostic and therapeutic development. Aims, Goals, Deliverables: We hypothesize that the local environment creates conditions for endometriotic lesions to develop and invade surrounding organs and that both the lesion and lesion-adjacent tissues contain factors that could represent viable targets for biomarker-based diagnostics and therapeutics. To investigate our hypothesis, we will employ cutting-edge technologies for investigating the gene-expression patterns of single cells (single cell RNA sequencing/Aim 1) and for high-resolution imaging to understand how different cell types comprising a tissue are spatially arranged (imaging mass cytometry/Aim 2). We will perform these experiments in human endometriotic lesions from the pelvic cavity, in tissue immediately adjacent to the lesion (to begin to understand the molecular features of the local environment), and in healthy endometrial tissue. We will use computational algorithms to compare the different gene expression patterns and to correlate these patterns with specific cell types. We will then analyze the spatial arrangement of these cell types to understand the cell-cell interactions that could help lesions to establish and grow. Applicability and Impact of Research: This work will yield the first comprehensive profile of the endometriosis “ecosystem” along with a list of expressed genes that researchers can use to form new hypotheses about disease etiology. This list of expressed genes will likely contain molecular factors that could be developed into biomarkers or therapeutic targets. Such outcomes could have immense clinical relevance and impact to the seven million civilian (three times the population of Chicago) and military women
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910130
Entities
People
- Elise T Courtois
Organizations
- Jackson Laboratory
- United States Army