Microbiota depletion ameliorates sickle cell induced vaso-occlusive crisis and organ damage

微生物群耗竭可改善镰状细胞引起的血管闭塞危机和器官损伤

基本信息

批准号：
9917576
负责人：
Huihui Li
金额：
$ 6.53万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-16 至 2022-03-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917576
关键词：
16S ribosomal RNA sequencing Acute Affect Aging American Anti-Bacterial Agents Anti-Inflammatory Agents Antibiotic Therapy Antibiotics Antioxidants Bacteria Blood Transfusion Blood Vessels Bone Marrow Transplantation Bypass Cause of Death Cell Adhesion Cell Adhesion Molecules Cell membrane Cells Cesarean section Cessation of life Chelating Activity Chronic Clinical Treatment DNA biosynthesis Data Defect Deferoxamine Development Diet Disease Disease Progression Erythrocytes Escherichia coli FDA approved Fetal Hemoglobin Functional disorder Genes Germ-Free Hematological Disease Hemolysis Homeostasis Hospitalization Human Hydroxamic Acids Hypoxia Immune response Inflammatory Inherited Injections Integrins Iron Iron Chelating Agents Iron Overload Laboratories Lead Life Macrophage-1 Antigen Mammalian Cell Mediating Mus Mutation Oral Organ Oxidants Pain Pathologic Pathology Patients Pharmaceutical Preparations Play Predisposition Probiotics Recombinant DNA Reporting Resolution Resources Role Sampling Sepsis Severities Severity of illness Sickle Cell Sickle Cell Anemia Signal Transduction Stress Testing Therapeutic Toxic effect Transplantation Treatment Efficacy United States Vendor Work aged alternative treatment base beta Globin congenic cost cost effective experimental study fecal microbiota host microbiome hydroxyurea inflammatory marker iron metabolism metal chelator microbial microbiome microbiota mouse model neutrophil novel premature sickling tissue injury vaso-occlusive crisis

16S ribosomal RNA sequencing Acute Affect Aging American Anti-Bacterial Agents Anti-Inflammatory Agents Antibiotic Therapy Antibiotics Antioxidants Bacteria Blood Transfusion Blood Vessels Bone Marrow Transplantation Bypass Cause of Death Cell Adhesion Cell Adhesion Molecules Cell membrane Cells Cesarean section Cessation of life Chelating Activity Chronic Clinical Treatment DNA biosynthesis Data Defect Deferoxamine Development Diet Disease Disease Progression Erythrocytes Escherichia coli FDA approved Fetal Hemoglobin Functional disorder Genes Germ-Free Hematological Disease Hemolysis Homeostasis Hospitalization Human Hydroxamic Acids Hypoxia Immune response Inflammatory Inherited Injections Integrins Iron Iron Chelating Agents Iron Overload Laboratories Lead Life Macrophage-1 Antigen Mammalian Cell Mediating Mus Mutation Oral Organ Oxidants Pain Pathologic Pathology Patients Pharmaceutical Preparations Play Predisposition Probiotics Recombinant DNA Reporting Resolution Resources Role Sampling Sepsis Severities Severity of illness Sickle Cell Sickle Cell Anemia Signal Transduction Stress Testing Therapeutic Toxic effect Transplantation Treatment Efficacy United States Vendor Work aged alternative treatment base beta Globin congenic cost cost effective experimental study fecal microbiota host microbiome hydroxyurea inflammatory marker iron metabolism metal chelator microbial microbiome microbiota mouse model neutrophil novel premature sickling tissue injury vaso-occlusive crisis

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项目摘要

Project Summary: As the most common inherited blood disorder in the United State, there are 70,000-100,000 Americans with sickle cell anemia. Sickle cell disease (SCD) is caused by a mutation in the β-globin gene, which leads to significant deformation red blood cell (RBC) membrane and promotes RBC adhesion to other cells to induce vaso-occlusive crises (VOC). Chronic sickle cell anemia is accompanied with progressive systemic multi- systemic organ dysfunction and cost over $475 million annually in hospital admission. Our laboratory has reported that sickle cell-induced hypoxic, oxidant, and inflammatory stress is perpetuated by aged neutrophils which positively correlates with VOC in humanized SCD mice. Our recent work has demonstrated that deletion of the microbiota in SCD mice by antibiotics restricted aged neutrophil expansion which consequently decreased VOC severity, and reduced organ damage as well as the iron overload. In addition, hydroxyurea, the only FDA- approved drug for SCD that promotes the anti-sickling fetal hemoglobin expression, also possesses anti- inflammatory, antiradical, and metal-chelating activities both in mammalian cells as well as in bacteria. In this application, we propose a 3-year experimental plan that will advance our understanding in the function of microbiota in SCD disease progression and will test whether manipulation of the microbiota will provide a potential novel SCD treatment. In Specific Aim 1, we will identify disease-modifying microbiota species that may contribute to neutrophil aging and SCD organ damage. 16S sequencing data has revealed microbiota differences between antibiotic treatment and untreated SCD mice, and the function of selected microbiota will be verified in germ-free SCD mice. In Specific Aim 2, we will examine if hydroxyurea reduces VOC and organ damage through microbiota manipulations in SCD mice in which fecal samples from hydroxyurea-treated and control SCD mice will be transplant to germ-free SCD to evaluate whether hydroxyurea-induced changes in the microbiota contribute to its therapeutic activity. In Specific Aim 3, we will study if iron restriction (by DFO or low-iron diet) or probiotics-induced changes in iron metabolism can ameliorate chronic organ damage in SCD mice. Iron-related changes in microbiota will be verified by germ-free SCD mice. These proposed studies, focused on strategies of microbiota manipulation in SCD, will allow us to identify the key microbial species that contribute to SCD pathophysiology, and provide potential novel cost-effective approaches for management of SCD’s life-long complications.

项目摘要：作为美国最常见的遗传性血液疾病，有70,000-100,000名美国人镰状细胞贫血。镰状细胞病（SCD）是由β-珠蛋白基因突变引起的，这导致明显的变形红细胞（RBC）膜，并促进RBC粘合剂诱导其他细胞以诱导血管熟悉的危机（VOC）。慢性镰状细胞贫血还伴有进行性全身性多每年入院的系统性器官功能障碍，耗资超过4.75亿美元。我们的实验室有报道了镰状细胞诱导的低氧，氧化剂和炎症性应激因衰老的中性粒细胞的持续这与人源化的SCD小鼠中的VOC积极相关。我们最近的工作证明了删除抗生素限制了衰老的中性粒细胞膨胀，在SCD小鼠中的微生物群降低 VOC严重程度，减少器官损伤以及铁超负荷。此外，羟基脲，唯一的FDA- 批准的SCD药物促进了抗触觉的胎儿血红蛋白表达，还具有抗哺乳动物细胞和细菌中的炎症，抗自由基和金属螯合活性。在此应用中，我们提出了一个为期3年的实验计划，该计划将提高我们对 SCD疾病进展中的微生物群，并将测试对微生物群的操纵是否会提供潜在的新型SCD治疗。在特定的目标1中，我们将确定可以改善疾病的微生物群，可能有助于中性粒细胞衰老和SCD器官损伤。 16S测序数据显示了微生物群的差异在抗生素治疗和未处理的SCD小鼠之间，选定的微生物群的功能将在无菌SCD小鼠。在特定目标2中，我们将检查羟基脲是否通过 SCD小鼠中的菌群操纵将移植到无菌SCD上，以评估羟基脲诱导的微生物群的变化是否有助于其治疗活动。在特定目标3中，我们将研究铁限制（通过DFO或低铁饮食）还是益生菌引起的铁代谢的变化可以改善SCD小鼠的慢性器官损伤。铁相关微生物群的变化将通过无菌SCD小鼠验证。这些拟议的研究着重于 SCD中的微生物群操纵将使我们能够识别有助于SCD的关键微生物物种病理生理学，并为管理SCD的终身管理提供了潜在的新颖具有成本效益的方法并发症。