Date of Award

12-15-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Didier Merlin

Second Advisor

Andrew Gewirtz

Third Advisor

Zhi-Ren Liu

Abstract

Inflammatory bowel disease (IBD), mainly including ulcerative colitis (UC) and Crohn’s disease (CD), has become a serious clinical problem in the developed countries. IBD is characterized by epithelial barrier disruption and alterations in immune regulation with symptoms of passive leaky diarrhea, fever, fatigue and abdominal pain. For the past few decades, significant numbers of investigations have been performed on IBD. However, there are still critical problems remain to be resolved. In our laboratory, we are interested in studying di-/tri- peptide transporter PepT1 and Ste20-like proline/alanine-rich kinase (SPAK). PepT1 and SPAK are believed to be highly involved in intestinal homeostasis and IBD. Insights into the function of PepT1 and SPAK are expected to facilitate a better understanding of gastrointestinal tract and IBD.

PepT1, a di/tri peptide transporter, is primarily expressed in the small intestine of healthy individuals. In the jejunum, PepT1 is particularly enriched in the well-differentiated absorptive epithelial cells in the villi. Studies of expression and function of PepT1 along the crypt-villus axis demonstrated that this protein is crucial to the process of di/tripeptide absorption. We recently exhibited that PepT1 plays an important role in multiple biological functions, including the ability to regulate the expression/secretion of specific microRNAs (miRNAs) and the expression levels of multiple proteins. Our results suggest that PepT1 contributes to maintain balance of homeostasis and proper functions in the small intestine, and dysregulated miRNAs and proteins along the crypt-villus axis are highly related to this process.

Furthermore, Ste20-like proline/alanine-rich kinase (SPAK) also plays a role in intestinal inflammation. My study has revealed that SPAK knockout (KO) significantly increases the intestinal trans-epithelial resistance and the expression of junction proteins as claudin-2 or E-cadherin. In murine models of colitis induced by dextran sulfate sodium and trinitrobenzene sulfuric acid, KO mice were more tolerant than WT mice. In conclusion, SPAK deficiency increases intestinal innate immune homeostasis, which is important for control or attenuation of pathological responses in inflammatory bowel diseases.

Collectively, PepT1 and SPAK both play significant role in maintaining intestinal homeostasis. With further investigation, they could be good target in study of new therapies on IBD.

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