IGEM:Stanford/ResearchProposal

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Project Description
The 2009 Stanford iGEM project centers on creating a device that will detect and respond to imbalances in specific subpopulations of T cells, a type of immune cell. The two populations of T cells that we are particularly interested in are Th17 cells, a branch of helper T cells that promote inflammatory responses, and regulatory T cells (Tregs), crucial for the generation and maintenance of localized immunosuppression. Distinct populations of Th17 cells and Tregs cells coexist and are reciprocally regulated in healthy tissue, and imbalances in the ratio of these lymphocytes have been implicated in a wide rage of autoimmune disorders including rheumatoid arthritis and irritable bowel diseases (IBD).

Our goal is to sense and correct such imbalances in individuals suffering from IBD by creating an Escherichia coli-based bacterial device that polarizes the differentiation of lymphocyte precursors along either the Th17 or Treg lineage. Our device will consist of two parts. The first part, our anti-inflammatory device, will control dangerous localized inflammation in the gut by detecting a byproduct linked to Th17-driven inflammation, nitric oxide, and excreting retinoic acid, a marker that inhibits the generation of Th17 cells. Likewise, the second, anti-immunosuppressive device, regulates Treg populations by detecting an analog of tryptophan, a target substrate of an enzyme involved in Treg immunosuppression, and secretes interleukin-6, a cytokine that inhibits Treg development.

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.

Project Overview
Homeostasis relies on a continual balance between Th17 cells, a branch of helper T-cells that promote inflammatory responses, and T-regulatory cells, the immunosuppressive response generator. However, when homeostasis is disrupted and the ratio of this cellular pair becomes imbalanced, the host becomes susceptible to autoimmunity. The 2009 Stanford iGEM project centers on creating a therapeutic probiotic intended to address the aberrant responses between these two T-cell subsets implicated in the etiology of one such autoimmune condition: Inflammatory Bowel Diseases (IBD).

A group of chronic inflammatory disorders that affect the gastrointestinal tract, IBD evolves from a complex mixture of genetic and environmental factors that remain incompletely elucidated. A risk factor that predisposes certain individuals to IBD, the composition of the gut’s commensal microbiota contributes to the initiation and prolongation of gastrointestinal inflammation 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. Our device will consist of two parts. The first part, our anti-inflammatory device, will redress 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, the second, anti-immunosuppressive device, 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.