The microbiome determines organ damage development in sickle cell disease

微生物组决定镰状细胞病的器官损伤发展

• 批准号: 10895168
• 负责人: Huihui Li
• 金额: $ 15.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-09-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10895168
• 关键词: Address; Affect; Africa South of the Sahara; American; Antibiotics; Antibodies; Area; Autoimmune; Bacteria; Bacterial Toxins; Bacterial Translocation; Belief; Blood Vessels; Bypass; Cause of Death; Cell Adhesion; Cell membrane; Cells; Cessation of life; Chronic; Circulation; Complex; Data; Deposition; Development; Development Plans; Diet; Dietary Iron; Disease Progression; Distant; Enterococcus gallinarum; Erythrocytes; Exhibits; Functional disorder; Genes; Germ-Free; Goals; Hematological Disease; Hemolysis; Hospitalization; IL17 gene; Immune system; Immunologic Stimulation; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Inherited; Intestinal permeability; Intestines; Iron; Iron Overload; Leaky Gut; Liver; Mediating; Microbe; Mucous body substance; Mus; Mutation; Organ; Oxidative Stress; Pain; Pathogenicity; Patients; Permeability; Portal vein structure; Probiotics; Renal function; Reporting; Research; Resources; Ribosomal DNA; Role; Sampling; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Specificity; Stress; Testing; Therapeutic; Tight Junctions; Training; Travel; United States; Up-Regulation; Vaccines; Work; beta Globin; biological adaptation to stress; career development; cost; cost effective; dietary control; dietary restriction; germ free condition; gut bacteria; gut microbiome; gut microbiota; improved; inflammatory marker; insight; iron metabolism; liver function; liver injury; microbial; microbial composition; microbiome; microbiome composition; microbiota; mouse model; murine colitis; novel; organ growth; pathogen; pathogenic bacteria; premature; prevent; recruit; treatment group

Project Summary: Sickle cell disease (SCD) is the most common inherited blood disorder in the United States, affecting 70,000- 100,000 Americans. SCD is caused by a mutation in the β-globin gene that leads to significant deformation of the red blood cell (RBC) membrane and promotes RBC adhesion to other cells, inducing vaso-occlusive episodes (VOE). Chronic SCD is accompanied by progressive, systemic multi-organ dysfunction and costs over $475 million annually in hospital admissions. Our recent work demonstrates that the depletion of microbiota in SCD mice by antibiotics reduces organ damage and iron overload. Our preliminary data show that organ damage is significantly improved in germ-free SCD mice compared to specific-pathogen-free SCD mice, confirming the importance of microbiota in organ damage development. Analysis by 16S rDNA sequencing uncovered a candidate bacterium—Enterococcus gallinarum (E. gallinarum)—that may promote organ damage in SCD mice. Additionally, we demonstrate that SCD mice fed an iron-restricted diet exhibit significant reversal of organ damage compared with SCD mice fed a control diet. In the current application, we propose a 5-year experimental plan to advance our understanding of the microbiota-mediated effects on SCD disease progression and to test the manipulation of microbiota as a potential novel SCD treatment. In Specific Aim 1, we will confirm whether E. gallinarum functions as a pathogenic bacterium to influence the progression of organ damage in SCD mice. Additionally, we will investigate whether an E. gallinarum–specific vaccine reduces organ damage burden in SCD mice. We will explore the microbiota- related mechanisms that induce organ damage in SCD mice. Specifically, we will study how microbiota can bypass the gut barrier by analyzing relevant gut permeability parameters such as tight junction and mucus layer integrity. We hypothesize that once E. gallinarum translocates from the portal vein to the liver, it upregulates T helper 17 (Th17) cells that recruit other inflammatory cells to induce the organ damage seen in SCD mice. In Specific Aim 2, we will explore the role of dietary iron in gut microbiota survival and whether dietary iron is involved in disrupting gut barrier integrity in 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 potentially provide novel, cost-effective approaches for managing SCD’s life-long complications.

项目概要： 镰状细胞病 (SCD) 是美国最常见的遗传性血液疾病，影响着 70,000 人。 10万美国人。 SCD 是由 β-珠蛋白基因突变引起的，导致球蛋白显着变形。 红细胞 (RBC) 膜并促进红细胞与其他细胞粘附，诱导血管闭塞 剧集（VOE）。慢性 SCD 伴有进行性、系统性多器官功能障碍，且费用超过 每年住院费用为 4.75 亿美元。 我们最近的工作表明，抗生素对 SCD 小鼠微生物群的消耗减少了器官损伤 损坏和铁过载。我们的初步数据表明，无菌条件下器官损伤得到显着改善 SCD 小鼠与无特定病原体的 SCD 小鼠进行比较，证实了微生物群在器官中的重要性 损害发展。 16S rDNA 测序分析发现了一种候选细菌——肠球菌 gallinarum (E. gallinarum)——可能会促进 SCD 小鼠的器官损伤。此外，我们证明 与喂养铁限制饮食的 SCD 小鼠相比，喂养限制铁饮食的 SCD 小鼠表现出显着的器官损伤逆转 控制饮食。 在当前的申请中，我们提出了一个为期 5 年的实验计划，以加深我们对 微生物群介导的对 SCD 疾病进展的影响并测试微生物群的操纵作为潜在的 新颖的 SCD 治疗方法。在具体目标 1 中，我们将确认鸡肠杆菌是否具有致病性 细菌影响 SCD 小鼠器官损伤的进展。此外，我们将调查是否 鸡肠杆菌特异性疫苗可减轻 SCD 小鼠的器官损伤负担。我们将探索微生物群—— 诱导SCD小鼠器官损伤的相关机制。具体来说，我们将研究微生物群如何 通过分析相关肠道通透性参数（例如紧密连接和粘液层）绕过肠道屏障 正直。我们假设一旦 E. gallinarum 从门静脉转移到肝脏，它就会上调 T 辅助 17 (Th17) 细胞招募其他炎症细胞以诱导 SCD 小鼠中出现的器官损伤。在 具体目标 2，我们将探讨膳食铁在肠道微生物群存活中的作用以及膳食铁是否 参与破坏 SCD 小鼠肠道屏障的完整性。这些拟议的研究重点关注以下战略： SCD 中的微生物群操控将使我们能够识别导致 SCD 的关键微生物物种 病理生理学，并可能为管理 SCD 的终生提供新颖的、具有成本效益的方法 并发症。