# Regulation of Intestinal Tight Junction Barrier and Inflammation by Autophagy

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2021 · $337,007

## Abstract

Project Summary
The long-term goal of our laboratory is to elucidate the molecular basis for intestinal homeostasis and its
dysregulation in intestinal inflammation, and to develop novel approaches for prevention and therapy of
inflammatory bowel diseases (IBD). The apically located inter-cellular tight junctions (TJ) within the intestinal
epithelium act as a paracellular barrier and prevent permeation of noxious luminal antigens. Loss of intestinal
TJ barrier function is a key pathogenic factor in intestinal disorders and IBD. Autophagy (macroautophagy) is
an intracellular degradation system that delivers unnecessary or dysfunctional cellular cargo sequestered
inside double-membrane vesicles (autophagosomes) to the lysosome. Emerging evidence shows that defects
in autophagy play an important role in the susceptibility, etiology, and progression of IBD. Although clinical data
and animal studies show a direct link between defective intestinal TJ barrier and intestinal inflammation in IBD
patients and animal models of IBD, the role of autophagy in the regulation of intestinal epithelial TJ barrier
remains unknown. Our preliminary studies indicated that autophagy plays a key role in the enhancement of
intestinal TJ barrier. Specifically, autophagy reduces paracellular TJ permeability by degradation of the pore
forming tight junction protein claudin-2 and increasing protein levels of barrier protective transmembrane TJ
protein occludin. Induction of autophagy causes a selective increase in lysosomal targeting of claudin-2 from
the membrane and causes an increase in membrane retention of occludin. Thus, our central hypothesis is that
autophagy selectively modulates TJ membrane protein composition to induce an enhancement of the intestinal
TJ barrier. We will address our hypothesis with the specific aims of (1) To delineate the intracellular vesicular
trafficking mechanisms in autophagy-induced enhancement of intestinal epithelial TJ barrier; (2) To elucidate
the mechanistic role of intracellular signaling in autophagy regulation of intestinal TJ barrier; and (3) To
delineate the protective role of autophagy-mediated enhancement of intestinal TJ barrier function in murine
models of IBD. We will use innovative technical tools such as in vivo siRNA technology, in vivo full length mice
colon perfusion, in vivo intestinal TJ protein trafficking, and high content quantitative imaging to study our
specific aims. This proposal will provide novel insights into the crucial role that autophagy plays in the
homeostasis of intestinal barrier and bridge the gap in scientific knowledge that will be important for therapeutic
efforts against IBD.

## Key facts

- **NIH application ID:** 10197898
- **Project number:** 5R01DK114024-05
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Prashant Nighot
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $337,007
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197898

## Citation

> US National Institutes of Health, RePORTER application 10197898, Regulation of Intestinal Tight Junction Barrier and Inflammation by Autophagy (5R01DK114024-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197898. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*