Use and identification of biomarkers for gastrointestinal diseases

Abstract

The described invention relates to the identification of biomarkers for gastrointestinal diseases and provides methods utilizing the biomarkers for in drug discovery, monitoring of treatment efficacy, and diagnostics. The invention further provides methods for identifying a therapeutic target to treat ulcerative colitis, colorectal cancer, and Crohn's disease.

Description

CROSS REFERENCES[0001]This application claims the benefit of priority to U.S. provisional application 61 / 195,646, filed 9 Oct. 2008, which is incorporated in its entirety herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to the identification of biomarkers for gastrointestinal diseases and further provides methods utilizing such biomarkers in drug discovery, the monitoring of treatment efficacy, and diagnostics.BACKGROUND OF THE INVENTION[0003]Components of the Human Gastrointestinal Tract[0004]The gastrointestinal tract is a continuous tube that extends from the mouth to the anus. On a gross level, the gastrointestinal tract is composed of the following organs: the mouth, most of the pharynx, the esophagus, the stomach, the small intestine (duodenum, jejunum and ileum), and the large intestine (cecum including the appendix, colon and rectum) (Tortora, G. J., et al., Principles of Anatomy and Physiology, Wiley & Sons, Inc. Hoboken, N.J. 2006). Each segmen...

AI Technical Summary

Benefits of technology

[0065]FIG. 11 shows RT-PCR amplicons derived from normal cells and gastrointestinal diseased cells. Lane 1: positive control; Lane 2: normal CRC cell line; Lane 3, diseased CRC cell line; Lane 4: non-active ulcerative colitis cell line; Lane 5: active ulcerative colitis cell line; Lane 6: non-active Crohn's disease cel

Problems solved by technology

There are no universally accepted molecular markers that identify gastrointestinal stem cells.

Many treatments focus on symptom relief, and are not curative.

The prognosis for patients with advanced CRC generally is poor.

Currently, no specific biomarker exists to aid in early diagnosis and / or management of CRC.

However, none of these genes or molecules have proved to be specific.

This partially may be due to the fact that studies that compare differential gene expression between tumor and normal colorectal epithelium have been limited by the lack of paired normal and tumor-derived colorectal epithelial cell lines from the same individual.

However, significant difficulties for identifying these biomarkers exist.

Additionally, many individuals do not avail themselves of colonoscopy (the best means of early detection) due to its costly and invasive nature.

Further, the vast majority of CRC biomarkers that have been discovered do not have a function in vivo, are not very effective in early detection of CRC, recognize only a small subset of cancers, and often only detect CRC after it has progressed to later stages and grades.

These models do not allow the identification of the specific cellular, molecular, and genetic changes that the colonic epithelium undergoes throughout its malignant transformation.

However, each of these model systems has limitations and differs markedly from an in vivo system of primary epithelial cells.

For example, malignant cell lines usually have chromosomal abnormalities that cause instability.

The use of freshly isolated epithelial cells often is complicated due to the mixture of several cell types present (T cells, B cells, or macrophages), especially when diseased tissue is used as cell source).

Furthermore, surface and crypt epithelial cells may have different phenotypes and functions and are not usually used in fully separated populations.

Similarly, findings with animal model systems show that these do not always mimic precisely the functional scenarios of human intestinal epithelial cells in vivo (Seshimo et al.

However, no such model has been available.

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