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.

项目概要 红细胞生成缺陷（红细胞 [RBC] 生成）导致的贫血是死亡率和死亡率的主要来源。 全世界的发病率。先天性红细胞生成不良性贫血 (CDA) 是一组晚期疾病 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- 英格斯。 CDAII 是最常见的 CDA 亚型，其次是 CDAI。 CDAII 是一种常染色体隐性遗传病 由 SEC23B 功能缺失突变引起，编码外壳蛋白复合物 2 的核心成分 (COPII) 囊泡，将分泌蛋白从内质网 (ER) 转运到高尔基体 比率。 CDAI 也是一种常染色体隐性遗传病，由编码 CDAN1 的功能丧失突变引起 CODANIN1，被认为在染色质组装中发挥作用。尽管鉴定出基因 CDAI 和 CDAII 潜在的缺陷，这些疾病的病理生理学仍然未知。 CODANIN1 有 已被证明与 SEC23B 在细胞内共定位，这表明 CDAI 和 CDAII 可能共享一个共同点。 常见或相关的分子发病机制。我们之前培育了具有造血功能 SEC23B 缺陷的小鼠； 这些小鼠没有表现出红细胞缺陷。接下来我们通过对酵母、斑马鱼、小鼠和人类的研究表明 SEC23B 在功能上与其密切相关的旁系同源物 SEC23A 重叠，并且表达 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 中的 SEC23A 和 SEC23B 水平与小鼠 BM 中的 SEC23A 和 SEC23B 水平相当）。本提案的总体目标 目的是表征 CDA 的分子发病机制。在早期的初步结果中，i）我们生成了小鼠 红细胞特异性组合 Sec23a/Sec23b 缺失；这些小鼠表现出深刻的红细胞表型； ii）我们还培育了具有造血功能 Cdan1 缺失的小鼠，这表明了深刻的血液学去- 效果。在本提案中，我们的目标是描述 CODANIN1 和 SEC23 在红细胞生成和红细胞生成中的关键作用。 定义 Cdan1 或组合 Sec23a/Sec23b 缺失导致的造血缺陷的程度。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 SEC23B 缺陷型与野生型红系细胞中 CODANIN1 的运输。此外，基于 ER- CDAII 中至高尔基体的转运缺陷以及某些酸化人血清中 CDAII RBC 的裂解，这表明 红细胞膜异常，我们假设 CDAII 是由一种或多种细胞运输受损引起的 红细胞质膜的关键货物蛋白。在初步结果中，我们证明了显着的消耗 与对照红细胞质膜相比，CDAII 中仅含有 5 种蛋白质。我们将通过定义来扩展我们的研究 在其他 CDAII 患者样本中分析这些货物的分泌，我们将确定这些货物的作用 参与 CDAII 的病理生理学。我们提出的研究对于理解 CDAs 的病理生理学，预计将为开发新疗法奠定基础 这些疾病可能与红细胞终末成熟缺陷引起的其他贫血有关。

项目成果

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

促红细胞生成素与血压、高血压和冠状动脉疾病的流行病学和遗传学关联。

• 发表时间: 2021
• 作者: Sun, Pengfei;Kumar, Nitin;Tin, Adrienne;Zhao, Jing;Brown, Michael R;Lin, Zesen;Yang, Min;Zheng, Qiwen;Jia, Jia;Bielak, Lawrence F;Yu, Bing;Boerwinkle, Eric;Hunker, Kristina L;Coresh, Josef;Chen, Y Eugene;Huo, Yong;Kardia, Sharon L R;K
• 通讯作者: K