F31 Mulero Russe

F31 穆莱罗·鲁斯

• 批准号: 10651644
• 负责人: Adriana Mulero-Russe
• 金额: $ 4.77万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651644
• 关键词: 3-Dimensional; Address; Adhesives; Adult; Affect; American; Architecture; Area; Basement membrane; Biochemical; Biocompatible Materials; Biological Products; Biophysics; Cell Therapy; Cells; Cellular Structures; Chemical Injury; Confocal Microscopy; Cues; Dependence; Development; Diameter; Disease model; Drug Screening; Elasticity; Encapsulated; Endoderm; Engineering; Engraftment; Epithelial Cells; Epithelium; Extracellular Matrix; Fiber Optics; Formulation; Foundations; Gene Expression; Generations; Growth; Growth Factor; Hindgut; Human; Hydrogels; Immunologic Deficiency Syndromes; In Situ; In Vitro; Inflammation; Inflammatory Bowel Diseases; Intestinal permeability; Intestines; Knowledge; Length; Ligands; Maleimides; Measures; Mechanics; Membrane; Mesenchymal; Mus; Organoids; Patients; Polymers; Process; Proliferating; Property; Rattus; Recovery; Reproducibility; Research; Resolution; Small Intestines; Source; Specific qualifier value; Structure; Technology; Therapeutic; Time; Tissues; Tube; Tumor-Derived; Ultraviolet Rays; Work; arm; cell type; clinical translation; clinically relevant; delivery vehicle; density; directed differentiation; epithelial repair; epithelial wound; ethylene glycol; experience; healing; human pluripotent stem cell; human stem cells; in vitro Model; in vivo; inflammatory milieu; injured; innovation; insight; intestinal crypt; intestinal epithelium; intestinal injury; matrigel; microbiota; monolayer; nutrient absorption; optical fiber; polarized cell; process repeatability; programs; repaired; self organization; stem cells; tissue repair; tool; translational potential; wound; wound healing

PROJECT SUMMARY Inflammatory Bowel Diseases (IBD) currently affect >1.6 million Americans. IBD is characterized by disruption to the intestinal epithelium and a high inflammatory environment. Available treatments target the inflammation through biological agents, however, fewer efforts have focused on epithelium healing and there are no broadly applicable therapies to repair intestinal epithelium. Human intestinal organoids (HIOs) are three-dimensional (3D) multicellular structures, derived from either adult intestinal stem cells or human pluripotent stem cells (hPSCs), that recapitulate human intestinal tissue architecture. HIOs are a promising cell source for intestinal epithelium repair, disease modeling, and drug screening. Previous work has demonstrated that HIOs engraft to the injured intestinal wall in vivo, however, these approaches are significantly limited by the lack of an appropriate delivery vehicle to drive HIO engraftment. HIO generation from hPSCs is multi-stage directed differentiation process comprising three stages: (I) differentiation into a definitive endoderm monolayer, (II) hindgut and primitive tube differentiation into free-floating, self-organized 3D aggregates (human intestinal spheroids, HIS), and (III) intestinal specification into HIOs within a 3D extracellular matrix. This in vitro culture process spans a 2D growth substrate (stage I and II) to a 3D matrix (stage III). Stage III requires culture within Matrigel, a murine tumor- derived basement membrane extract with ill-defined composition, lot-to-lot variability, and limited clinical translation potential. Another roadblock to HIO technologies is the low yield and consistency of HIS differentiation in HIOs. The objectives of this project are to (1) engineer a synthetic hydrogel platform with independent control of the biochemical and biophysical cues guiding the entire in vitro differentiation of hPSCs into HIOs, and (2) deliver HIOs in a synthetic coating to intestinal injuries in vivo. The central hypothesis is that an engineered synthetic matrix with appropriate biophysical and biochemical cues will support the HIO self-organization, growth, and differentiation process and enhance HIO engraftment and healing of intestinal wounds. Aim 1: Engineer a 2D synthetic matrix promoting spheroid generation from hPSCs. Aim 2: Evaluate the maturation of HIOs from the generated spheroids within synthetic niches. Aim 3: Engineer a clinically translatable therapeutic delivery material for HIOs to injured intestinal tissue. The results of this study will increase the clinical relevance the generated HIOs and will provide a scalable and translatable synthetic material for the differentiation and delivery of HIOs.

项目总结