Investigations of the gastrointestinal tract in development and disease / Ayano Kondo.

Format:

Book

Thesis/Dissertation

Author/Creator:

Kondo, Ayano, author.

Contributor:

Kaestner, Klaus H., degree supervisor.

University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Cellular biology.

Molecular biology.

Immunology.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Local Subjects:

Cellular biology.

Molecular biology.

Immunology.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Physical Description:

1 online resource (159 pages)

Contained In:

Dissertations Abstracts International 83-08B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2021.

Language Note:

English

System Details:

Mode of access: World Wide Web.

Summary:

The intestine is a highly dynamic organ with diverse functions that are essential for human health, and disruption of the homeostatic processes involved in intestinal function causes a number of diseases, such as colorectal cancer, celiac disease, and inflammatory bowel disease (IBD). However, there are still many gaps in our knowledge of intestinal biology, ranging from the mechanisms of intestinal development, the signaling networks involved in maintaining intestinal epithelial homeostasis, and the mechanisms of complex diseases such as IBD. Thus, there is still a lot of work that needs to be done to better understand the biology of the intestine, which would ultimately benefit intestinal disease research and therapeutic development.This thesis contains two distinct studies that address knowledge gaps in intestinal research. First, I investigated the mechanisms by which the structure of the intestine is refined during embryonic development, using a conditional genetic ablation mouse model for a critical signaling molecule. Specifically, FOXL1+ expressing mesenchymal cells, which constitute the sub-epithelial layer of the intestine from the stomach to the colon, express key components of the Wnt signaling pathway and are important for maintaining the intestinal stem cell niche in adult mice. Interestingly, these cells also express WNT5A, a major non-canonical Wnt ligand that is essential for embryonic intestinal development but whose cell type of action was previously undetermined. For my thesis work, I derived Foxl1-Cre; Wnt5af/f mice for cell-type specific deletion of Wnt5a solely in epithelium-proximal mesenchymal cells and assessed the consequences to embryonic development. My results showed that although epithelial structural integrity was not lost, ablation of WNT5A in FOXL1+ cells is sufficient to cause shortening of the midgut due to increased epithelial apoptosis during fetal development.My second project utilized a multiplexed imaging technique called Imaging Mass Cytometry (IMC) to study the cellular and proteomic profiles of IBD tissues. IBD is a highly heterogeneous disease that leads to disruption of homeostasis of the immune response, causing chronic inflammation of the intestinal mucosa. While there are several therapies available for IBD patients, there is still a large unmet need for those individuals who do not respond to the currently available treatments. Thus, development of novel therapeutics requires improved disease stratification based on deeper characterization of the inflamed mucosa. IMC can quantify multiple antigens and cell types of the intestine while maintaining spatial resolution for assessment of cell-to-cell interactions within disease tissue. I performed multiplexed image analysis of 12 IBD and 12 healthy control samples, for which I was able to identify and quantify major immune cell types, their expression markers, and the cell-cell interaction enrichment between regulatory T cells (Tregs) and other immune cells. This study is an important steppingstone for future spatially resolved analysis of IBD.

Notes:

Source: Dissertations Abstracts International, Volume: 83-08, Section: B.

Advisors: Kaestner, Klaus H.; Committee members: Hamilton, Kathryn E.; Lengner, Christopher J.; Morrisey, Edward E.

Department: Cell and Molecular Biology.

Ph.D. University of Pennsylvania 2021.

Local Notes:

School code: 0175

ISBN:

9798780657538

Access Restriction:

Restricted for use by site license.

This item must not be sold to any third party vendors.