Dkk1-Endothelial Progenitor Cell Treatment for the Mitigation of Hematopoietic Radiation Injury

Dkk1-内皮祖细胞治疗减轻造血放射损伤

基本信息

批准号：
10163351
负责人：
Heather A Himburg
金额：
$ 31.2万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
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：
2018-03-12 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163351
关键词：
Acute Address Allogenic Anemia Angiogenic Factor Animals Area Autologous Blood Vessels Bone Marrow Bone Marrow Aspiration CD34 gene CSF3 gene Cause of Death Cell Line Cell Therapy Cells Cessation of life Clinical Cryopreservation Data Dose Endothelial Cells Endothelium Epidermal Growth Factor Event Exposure to Failure Filgrastim Funding Opportunities Goals Growth Factor Hematology Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hemorrhage Homologous Transplantation Hour Human Human Resources In Vitro Individual Infection Infusion procedures Injury Laboratories Mediating Modeling Mus National Institute of Allergy and Infectious Disease Natural regeneration Nuclear Nuclear Accidents Organ PGF gene Patients Production Radiation Radiation Injuries Radiation Toxicity Radiation exposure Radiology Specialty Recovery Research Role Safety Saline Source Syndrome System Testing Therapeutic Time Toxic effect Transplantation Treatment Efficacy Umbilical Cord Blood VEGFA gene Whole-Body Irradiation Work Xenograft Model base cell bank clinically relevant cytokine differential expression efficacy testing endothelial stem cell experience gastrointestinal improved in vitro Assay in vivo jagged1 protein loss of function mass casualty mesenchymal stromal cell metropolitan neutrophil novel peripheral blood pleiotrophin progenitor radiation mitigation regenerative standard of care stem cells

项目摘要

Project Summary This project proposes to assess whether administration of Dkk1-treated endothelial progenitor cells (Dkk1- EPCs) mitigates radiation injury to the bone marrow by promoting concomitant vascular and hematopoietic recovery. The ultimate goal of this work is to develop a cell therapy that can be administered >48 hours after injury to rescue victims of radiation exposure from death due to hematopoietic toxicities such as infection, anemia, and hemorrhage. This is clinically relevant as there are likely to be several hundred thousand victims with acute hematopoietic toxicities if a large-scale nuclear or radiological terror attack were to occur. In a mass casualty scenario, treatment is likely to be delayed due to the large volume of victims; however, the current standard of care Neupogen (G-CSF) only has proven survival benefit when administered with the first 24 hours. Therefore, we propose to characterize a novel cell-based rescue therapy for mitigation of radiation injury to the bone marrow. Past work from our laboratory and others has shown that infusion of endothelial cells can accelerate hematopoietic recovery and rescue lethally irradiated mice from death due to hematopoietic syndrome. In this proposal, we show that pre-treatment with Dkk1 stimulates endothelial cells to produce regenerative and angiogenic factors such as epidermal growth factor. Furthermore, we show that allogeneic transplantation of Dkk1-treated EPCs (Dkk1-EPCs) significantly improved vascular and hematopoietic recovery following 5 Gy total body irradiation compared to saline or EPC treatment alone. Based on these findings, we hypothesize that Dkk1-EPCs are a potential cellular therapeutic for the mitigation of hematopoietic toxicities in ARS vicitims. To test this hypothesis, we propose the following specific aims: 1) Determine whether systemic administration of Dkk1-EPCs improves survival in lethally irradiated mice. 2) Determine whether Dkk1-EPCs mitigate injury to irradiate human BM CD34+ cells. 3) Develop a clinical resource of human EPCs. 4) Determine the cellular mechanisms through which Dkk1-EPCs promote regeneration in irradiated mice.

项目概要该项目拟评估是否给予经 Dkk1 处理的内皮祖细胞（Dkk1- EPCs）通过促进血管和造血来减轻骨髓的辐射损伤恢复。这项工作的最终目标是开发一种可以在治疗后 48 小时以上进行的细胞疗法。因造血毒性（例如感染）而导致辐射暴露受害者免于死亡的伤害，贫血、出血。这与临床相关，因为可能有数十万受害者如果发生大规模核或放射性恐怖袭击，会产生急性造血毒性。在群众中伤亡情况下，由于受害者人数较多，治疗可能会被延误；然而，目前的标准护理 Neupogen (G-CSF) 仅在前 24 次给药时才被证明具有生存益处小时。因此，我们建议描述一种新型的基于细胞的救援疗法，以减轻辐射损伤骨髓。我们实验室和其他实验室过去的工作表明，内皮细胞的输注可以加速造血功能恢复并挽救因造血综合征而死亡的受致命辐射的小鼠。在这个提案中，我们表明用 Dkk1 进行预处理可以刺激内皮细胞产生再生和血管生成因子，例如表皮生长因子。此外，我们还发现同种异体移植 Dkk1 处理的 EPC (Dkk1-EPC) 在 5 Gy 后显着改善血管和造血恢复与单独的盐水或 EPC 治疗相比，全身照射。根据这些发现，我们假设 Dkk1-EPC 是一种潜在的细胞疗法，可减轻 ARS 受害者的造血毒性。为了检验这一假设，我们提出以下具体目标：1）确定是否全身给药 Dkk1-EPCs 可以提高受到致命辐射的小鼠的存活率。 2) 确定 Dkk1-EPCs 是否减轻对照射人骨髓 CD34+ 细胞。 3）开发人类EPC的临床资源。 4) 确定蜂窝 Dkk1-EPCs 促进受辐射小鼠再生的机制。