Progenitor cell based therapy to mitigate radiation induced gastro intestinal syndrome

基于祖细胞的疗法可减轻辐射诱发的胃肠综合症

基本信息

批准号：
10360605
负责人：
Subhrajit Saha
金额：
$ 50.95万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-07 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10360605
关键词：
Abdomen Acute Adult Allogenic Animals Antibiotics Bone Marrow Bone Marrow Transplantation CSF3 gene Cell Differentiation process Cell Proliferation Cell Therapy Cells Conditioned Culture Media Cryopreservation DNA Damage Data Defect Development Dose Epithelial Exposure to FDA approved Feedback Filgrastim Genetic Granulocyte Colony-Stimulating Factor Hematopoietic Hour Human Hydration status Immunodeficient Mouse Individual Injury Intestinal Mucosa Intestines Ionizing radiation KRT19 gene LGR5 gene Licensure Ligands Modeling Multiple Organ Failure Mus Myeloid Cells Natural regeneration Nuclear Nuclear Accidents Organ Organoids Paracrine Communication Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacology Population Predisposition Proliferating Radiation Radiation Accidents Radiation Dose Unit Radiation Injuries Radiation Tolerance Radiation Toxicity Radiation exposure Radiation induced damage Radiation-Protective Agents Reporting Research Risk Role Schedule Signal Transduction Supportive care Syndrome Testing Therapeutic Intervention Therapeutic Uses Time Tissue Model Tissues Transplantation Vesicle WNT Signaling Pathway Whole-Body Irradiation acute toxicity animal rule antagonist cell type epithelial repair epithelium regeneration extracellular vesicles gastrointestinal granulocyte improved intestinal epithelium irradiation lead candidate liposomal delivery macrophage medical countermeasure mortality novel peripheral blood progenitor radiation mitigation radiation-induced tissue damage regenerative repaired self-renewal small hairpin RNA standard of care stem cell growth stem cell niche stem cell population stem cell self renewal stem cells

项目摘要

Project Summary: Currently, there is a need for strategies that mitigate acute radiation-induced gastrointestinal syndrome (RIGS). The risk of large populations encountering radiation exposure is real and growing. Although a few drugs are available which can protect radiation injury if applied prior to radiation exposure, to date there are no agents available which can be applied 24 hr post-exposure to mitigate the acute radiation syndrome. The high radiosensitivity of the intestinal epithelium increases susceptibility to RIGS; and with mortality within 10-15 days there is limited time for therapeutic intervention. We have developed a human peripheral blood mono nuclear cell derived macrophage committed progenitor (MCP) cell therapy which can mitigate RIGS and improve survival when applied 24 hr after an otherwise lethal dose of radiation exposure. These progenitor cells are modulated ex-vivo to increase expression of WNT ligand, a major paracrine signal for intestinal epithelial regeneration. In this project we will fully characterize this novel cell therapy with a determination of an optimum dose and schedule for mitigation of RIGS. We will examine the general applicability of this strategy in young and radiosensitive animals. Finally we will evaluate the involvement of MCP derived WNT signaling in repair and regeneration of intestinal stem cells.

项目概要：目前，需要减轻急性辐射诱发胃肠道综合征（RIGS）的策略。大量人口遭受辐射照射的风险是真实存在的，而且还在不断增加。虽然有一些药物如果在辐射暴露之前使用，可以保护辐射损伤，但迄今为止还没有任何药物可以在照射后 24 小时使用，以减轻急性辐射综合症。高肠上皮的放射敏感性增加了对 RIGS 的易感性；并在 10-15 天内死亡治疗干预的时间有限。我们开发了人外周血单核细胞细胞源性巨噬细胞定型祖细胞 (MCP) 细胞疗法可减轻 RIGS 并提高生存率在接受致命剂量的辐射照射 24 小时后使用。这些祖细胞受到调节离体增加 WNT 配体的表达，WNT 配体是肠上皮再生的主要旁分泌信号。在在这个项目中，我们将通过确定最佳剂量和时间表来充分描述这种新型细胞疗法的特征用于缓解 RIGS 的影响。我们将研究该策略在年轻人和放射敏感人群中的普遍适用性动物。最后，我们将评估 MCP 衍生的 WNT 信号传导在细胞修复和再生中的参与情况。肠道干细胞。