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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

基本信息

批准号：
10407619
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
项目类别：
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/10407619
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 Definity 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 base deletion analysis improved in vivo loss of function mutation man mortality mouse genetics novel therapeutics paralogous gene protein complex secretory protein trafficking vesicle transport

项目摘要

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.

项目总结