The molecular pathophysiology of the congenital dyserythropoietic anemias

先天性红细胞生成障碍性贫血的分子病理生理学

• 批准号: 10618313
• 负责人: Rami Khoriaty
• 金额: $ 61.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618313
• 关键词: Abnormal Red Blood Cell; Alleles; Anemia; Biotinylation; Bone Marrow; CRISPR/Cas technology; Capsid Proteins; Cell membrane; Cells; Characteristics; Chromatin Modeling; Chronic Kidney Failure; Complete Blood Count; Congenital dyserythropoietic anemia; Cytolysis; Defect; Development; Disease; Endoplasmic Reticulum; Erythroblasts; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Evolution; Exhibits; Fetal Liver; Flow Cytometry; Foundations; Functional disorder; Genetic; Genetic Diseases; Genetic Models; Golgi Apparatus; Hematology; Hematopoietic; Histology; Human; Impairment; Inflammatory; K562 Cells; Knowledge; Malignant Neoplasms; Mass Spectrum Analysis; Molecular; Morbidity - disease rate; Morphology; Mus; Mutation; Pathogenesis; Patients; Pattern; Peripheral; Phenotype; Plasma Cells; Play; Production; Proteins; Role; Sampling; Source; Therapeutic; Vesicle; Work; Yeasts; Zebrafish; autosome; comparison control; improved; in vivo; loss of function mutation; mortality; mouse genetics; novel therapeutics; paralogous gene; protein complex; secretory protein; trafficking; vesicle transport

Project Summary Anemia due to defects in erythropoiesis (red blood cell [RBC] production) is a major source of mortality and morbidity worldwide. The Congenital Dyserythropoietic Anemias (CDAs) are a group of disorders of terminal erythroid maturation defects characterized by ineffective erythropoiesis and distinctive bone marrow (BM) find- ings. CDAII is the most common CDA subtype, followed by CDAI. CDAII is an autosomal recessive disease resulting from loss-of-function mutations in SEC23B, encoding a core component of coat protein complex-2 (COPII) vesicles, which transport secretory proteins from the Endoplasmic reticulum (ER) to the Golgi appa- ratus. CDAI, also an autosomal recessive disease, results from loss-of-function mutations in CDAN1, encoding CODANIN1, which is proposed to play a role in chromatin assembly. Despite the identification of the genetic defects underlying CDAI and CDAII, the pathophysiology of these disorders remains unknown. CODANIN1 has been shown to co-localize intracellularly with SEC23B, suggesting that CDAI and CDAII might share a com- mon or related molecular pathogenesis. We previously generated mice with hematopoietic SEC23B deficiency; these mice did not exhibit a RBC defect. We next showed through studies in yeast, zebrafish, mice, and hu- man cells that SEC23B overlaps in function with its closely related paralog, SEC23A, and that the expression pattern of the SEC23 paralogs has shifted in evolution (SEC23B is the predominantly expressed paralog in human BM, with comparable SEC23A and SEC23B levels in mouse BM). The overall objective of this proposal is to characterize the molecular pathogenesis of the CDAs. In early preliminary results, i) we generated mice with erythroid-specific combined Sec23a/Sec23b deletion; these mice exhibit a profound erythroid phenotype; ii) we also generated mice with hematopoietic Cdan1 deletion, which demonstrate a profound hematologic de- fect. In this proposal, we aim to characterize the critical roles of CODANIN1 and SEC23 in erythropoiesis and define the extent of the hematopoietic defect resulting from Cdan1 or combined Sec23a/Sec23b deletion. We also aim to define the genetic interaction between Sec23b and Cdan1 in vivo and determine the intracellular trafficking of CODANIN1 in SEC23B-deficient versus wild-type erythroid cells. Furthermore, based on the ER- to-Golgi transport defect in CDAII and on the lysis of CDAII RBC in some acidified human sera, which suggests an RBC membrane abnormality, we hypothesize that CDAII results from impaired trafficking of one or more key cargo proteins to the RBC plasma membrane. In preliminary results we demonstrate significant depletion of only 5 proteins in CDAII compared to control RBC plasma membranes. We will expand our studies by defin- ing the secretion of these cargos in additional CDAII patient samples and we will identify the roles of these car- gos in the pathophysiology of CDAII. Our proposed studies have important implications for understanding the pathophysiology of the CDAs and are expected to lay the foundation for the development of novel therapies for these disorders, which may be relevant to other anemias resulting from defective terminal erythroid maturation.

项目摘要 由于促红细胞生成缺陷引起的贫血（红细胞[RBC]生产）是死亡率的主要来源 全球发病率。先天性颗粒嗜性贫血（CDA）是一组终端疾病 红细胞成熟缺陷，其特征是无效的红细胞生成和独特的骨髓（BM）发现 - s。 CDAII是最常见的CDA亚型，其次是CDAI。 CDAII是一种常染色体隐性疾病 由SEC23B的功能丧失突变导致，编码外套蛋白质复合物的核心成分2 （copii）囊泡，将分泌蛋白从内质网（ER）传递到高尔基 比塔斯。 CDAI也是一种常染色体隐性疾病，是由CDAN1中功能丧失突变引起的 Codanin1，提议在染色质组装中发挥作用。尽管确定了遗传 CDAI和CDAII的缺陷，这些疾病的病理生理仍然未知。 Codanin1具有 已显示与Sec23b近距离地进行局部定位，这表明CDAI和CDAII可能共享 MON或相关的分子发病机理。我们以前以造血SEC23B缺乏产生了小鼠； 这些小鼠没有表现出RBC缺陷。接下来，我们通过在酵母，斑马鱼，小鼠和Hu-的研究中进行的研究表明 Sec23b与其紧密相关的旁系同源物和Sec23a的人细胞重叠，并且该表达式 Sec23旁系同源物的模式在进化中发生了变化（Sec23b是主要表达的旁系同源物 人BM，小鼠BM中具有可比的Sec23a和Sec23b水平）。该提议的总体目标 是为了表征CDA的分子发病机理。在早期初步结果中，i）我们生成了小鼠 与红细胞特异性的SEC23A/SEC23B缺失合并；这些小鼠表现出深刻的红斑表型。 ii）我们还产生了造血CDAN1缺失的小鼠，这证明 fect。在此提案中，我们旨在表征codanin1和sec23在红细胞生成和 定义由CDAN1或SEC23A/SEC23B缺失组合产生的造血缺陷程度。我们 还旨在定义体内Sec23b和CDAN1之间的遗传相互作用，并确定细胞内 在Sec23b缺陷型与野生型红细胞细胞中的codanin1的运输。此外，基于 在CDAII和CDAII RBC裂解的某些酸化人血清中的Golgi转运缺陷，这表明 RBC膜异常，我们假设CDAII是由于一个或多个贩运受损而导致的 RBC质膜的关键货物蛋白。在初步结果中，我们证明了明显的耗竭 与对照RBC质膜相比，CDAII中只有5种蛋白质。我们将通过定义扩展我们的研究 在其他CDAII患者样品中分泌这些货物，我们将确定这些货物的作用 CDAII病理生理学中的GO。我们提出的研究对理解 CDA的病理生理学，并有望为开发新疗法的基础 这些疾病，这可能与终末红细胞成熟有缺陷导致的其他贫血有关。

项目成果

Epidemiologic and Genetic Associations of Erythropoietin With Blood Pressure, Hypertension, and Coronary Artery Disease.

• DOI: 10.1161/hypertensionaha.121.17597
• 发表时间: 2021-11
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Sun P;Kumar N;Tin A;Zhao J;Brown MR;Lin Z;Yang ML;Zheng Q;Jia J;Bielak LF;Yu B;Boerwinkle E;Hunker KL;Coresh J;Chen YE;Huo Y;Kardia SLR;Khoriaty R;Zhou X;Morrison AC;Zhang Y;Ganesh SK
• 通讯作者: Ganesh SK