Team:Stanford/ProjectPage

Abstract

Inflammatory bowel disease, a chronic inflammatory disorder that affects the gastrointestinal tract, evolves from a complex mixture of genetic and environmental factors that remain incompletely elucidated. A risk factor that predisposes certain individuals to IBD is the composition of the gut’s commensal microbiota and its contribution to the initiation and prolongation of gastrointestinal inflammation. This occurs by inducing deviant responses from the pro-inflammatory Th17 and suppressive Treg lineages. Our goal is to sense and correct such imbalances in individuals suffering from IBDs by creating an Escherichia coli-based bacterial device that polarizes immune cells to have directed differentiation along either the Th17 or T-regulatory lineage from a single CD4 cell population. Our device will consist of two parts. An anti-inflammatory device that redresses injurious gastrointestinal inflammation by detecting a byproduct of Th17 cell proliferation, nitric oxide, and excreting retinoic acid, a marker that down regulates Th17 populations. Likewise, an anti-immunosuppressive device that regulates T-regulatory populations by detecting an analog of tryptophan, a target substrate of T-regulatory markers, and emits interleukin-6, a cytokine that down regulates T-regulatory cells.

We envision our proposed machine as a novel and directed probiotic therapy that will act at the interface between commensal bacteria and human lymphocytes while integrating cutting-edge immunology with synthetic biology.

You can view our project on a more specific breakdown by viewing the pdf Systems Overview

Background/Significance

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Biology behind the mechanism we are going to manipulate (explain retinoic acid, tryyp, beta carotine, etc...

Having established the clinical significance of the project, the team’s task was to develop a solution that addresses the weaknesses of current treatments for IBD. Instead of ameliorating IBD symptoms through drugs that need to be taken periodically or through invasive surgical procedures, the team decided to tackle IBD at the source by designing a device to regulate the Th17 and Treg cell populations whenever the device senses an imbalance between the subpopulations.

First, the team identified two markers of Th17 and Treg activity: nitric oxide and L-tryptophan levels. The team’s device senses concentration levels of these two markers to determine whether the Th17 and Treg populations are imbalanced. If they are imbalanced, the device will need to produce factors to balance the populations.

The team next identified two factors, retinoic acid and Interleukin – 6, that can control production of Th17 and Treg cells in vivo, and the team’s device is designed to produce these two factors to regulate Th17 and Treg populations.

The team decided to use E. coli as the chassis to produce and sense these molecular factors. The advantages of using E. coli are that E. coli are well characterized, straightforward to engineer, and perhaps most importantly, native to the human gut flora. This last point ultimately enables our device to be assimilated into an IBD patient’s digestive tract, in close proximity to the sites of disease the device is targeted to treat.

However, a disadvantage of using E. coli is that it is difficult to design an E. coli chassis that can simultaneously produce two different molecules and sense two different markers.

Thus the team divided the sensing and production between two E. coli devices, shown here as Device 1 and Device 2. As will be explained in more detail later, these two E, coli devices sense opposite imbalances between Th17 and Treg cells and respond by producing factors that exert appropriate effects to bring the populations back into balance.

Previously, we presented two ways cell populations can be imbalanced: too many Th17 cells compared to Tregs, which can result in IBD, and too many Tregs compared to Th17 cells, which can result in excess immunosuppression.

We tailored Device 1 to respond to excess Th17 cells and inflammation. Device 2 is tailored to respond to excess Treg cells and immunosuppression.

Let us begin with Device 1. We want this device to treat inflammation (specifically IBD) due to excess Th17 cells.

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symbols and how you assigned them, refer to project using these symbols throughout rest of page)

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Device 1: Anti-Inflammatory Device

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Device 2: Anti-Immunosuppressive Device

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Modeling--short explanation of purpose and significant findings, then link to that page

Results

Analysis

Conclusions