Creating a niche for engineered live biotherapeutics

为工程活生物治疗创造利基市场

• 批准号: 10427447
• 负责人: Thomas J Mansell
• 金额: $ 29.07万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427447
• 关键词: Bacteria; Biological Response Modifier Therapy; Carbohydrates; Carbon; Cells; Coculture Techniques; Complex; Drug Delivery Systems; Engineering; Environment; Enzymes; Escherichia coli; Goals; Growth; Human; In Vitro; Injections; Lactococcus lactis; Libraries; Methods; Mus; Organoids; Outcome; Peptides; Pharmaceutical Preparations; Phenotype; Population; Production; Proteins; Small Intestines; Source; System; Testing; Therapeutic; delivery vehicle; disease diagnosis; fitness; gene product; genome-wide; improved outcome; in vivo; interest; prebiotics; public health relevance; small molecule; small molecule therapeutics

PROJECT SUMMARY The long-term goal of this proposal is to improve outcomes of delivery of small molecules, peptides, and proteins to the human gut by engineered live biotherapeutic bacteria. To accomplish this, we will use two strategies to optimize biotherapeutic growth in the gut environment. First, we will match prebiotic compounds (complex carbohydrates not digested by the body) with heterologous expression of enzymes that allow cells to utilize these privileged carbon sources. Second, we will create genome-scale libraries in our candidate biotherapeutics, E. coli Nissle 1917 and Lactococcus lactis, to identify gene products that increase fitness in the gut and gut-like environments. The methods will be tested in in vitro culture, small intestinal organoid co-culture, and in vivo in the mouse gut to determine enrichment of the biotherapeutic population, enhanced production of the therapeutic small molecule, peptide, or protein of interest, and phenotypic outcome in systems of increasing verisimilitude to the human gut.

项目总结