A5045998440- Erythrocyte Function and Pathophysiology
- Complement system in diseases
- Platelet Disorders and Treatments
- CRISPR and Genetic Engineering
- Blood Coagulation and Thrombosis Mechanisms
- Hemoglobinopathies and Related Disorders
- Hemophilia Treatment and Research
- Erythropoietin and Anemia Treatment
- Cellular transport and secretion
- Blood properties and coagulation
- Blood groups and transfusion
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Blood disorders and treatments
- Protease and Inhibitor Mechanisms
- Zebrafish Biomedical Research Applications
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- PARP inhibition in cancer therapy
- Genetic Associations and Epidemiology
- Calcium signaling and nucleotide metabolism
- Hippo pathway signaling and YAP/TAZ
- Ubiquitin and proteasome pathways
- Autophagy in Disease and Therapy
- Neuropeptides and Animal Physiology
- Glycosylation and Glycoproteins Research
Howard Hughes Medical Institute
2006-2024
University of Michigan
2007-2024
Imperial College London
2005
Approximately one-third of the mammalian proteome is transported from endoplasmic reticulum-to-Golgi via COPII-coated vesicles. SEC23, a core component coat protein-complex II (COPII), encoded by two paralogous genes in vertebrates (Sec23a and Sec23b). In humans, SEC23B deficiency results congenital dyserythropoietic anemia type-II (CDAII), while SEC23A skeletal phenotype (with normal red blood cells). These distinct clinical disorders, together with previous biochemical studies, suggest...
The zebrafish is a powerful model for studying vascular development, demonstrating remarkable conservation of this process with mammals. Here, we identify mutant, redhead ( rhd mi149 ), that exhibits embryonic CNS hemorrhage intact gross development the vasculature and normal hemostatic function. We show phenotype caused by hypomorphic mutation in p21-activated kinase 2a pak2a ). PAK2 acts downstream Rho-family GTPases CDC42 RAC has been implicated angiogenesis, regulation cytoskeletal...
Glycans on mucosal surfaces have an important role in host-microbe interactions. The locus encoding the blood-group-related glycosyltransferase β-1,4-N-acetylgalactosaminyltransferase 2 (B4galnt2) is subject to strong selective forces natural house-mouse populations that contain a common allelic variant confers loss of B4galnt2 gene expression gastrointestinal (GI) tract. We reasoned altered glycan-dependent intestinal interactions may underlie these signatures selection. To determine...
The complete array of genes required for terminal erythroid differentiation remains unknown. To address this knowledge gap, we perform a genome-scale CRISPR knock-out screen in the human progenitor cell line HUDEP-2 and validate candidate regulators custom secondary screen. Comparison sgRNA abundance library, proerythroblasts, orthochromatic erythroblasts, resulted identification that are essential proerythroblast survival differentiation. Among top identified known erythropoiesis,...
ABSTRACTErythropoietin (EPO) stimulates erythroid differentiation and maturation. Though the transcriptional regulation of EPO has been well studied, molecular determinants secretion remain unknown. Here, we generated a HEK293T reporter cell line that provides quantifiable selectable readout intracellular levels performed genome-scale CRISPR screen identified SURF4 as an important mediator secretion. Targeting with multiple independent single guide RNAs (sgRNAs) resulted in accumulation...
The metalloprotease ADAMTS13 cleaves von Willebrand factor (VWF) in circulating blood, limiting the size of VWF multimers and regulating activity. Abnormal regulation contributes to bleeding thrombotic disorders. levels plasma are highly variable among healthy individuals, although heritability genetic determinants this variation unclear. We performed genome-wide association studies concentrations 3244 individuals from 2 independent cohorts individuals. was between 59.1% (all individuals)...
The RIIIS/J inbred mouse strain is a model for type 1 von Willebrand disease (VWD), common human bleeding disorder. Low factor (VWF) levels in are due to regulatory mutation, Mvwf1, which directs tissue-specific switch expression of glycosyltransferase, B4GALNT2, from intestine blood vessel. We recently found that Mvwf1 lies on founder allele among laboratory strains. To investigate the evolutionary forces operating at B4galnt2, we conducted survey DNA sequence polymorphism and...
The COPII component SEC23A overlaps functionally with its paralogous protein and rescues the SEC23B-deficient CDAII defect.
Thrombopoietin (TPO) is a plasma glycoprotein that binds its receptor on megakaryocytes (MK) and MK progenitors, resulting in enhanced platelet production. The mechanism by which TPO secreted from hepatocytes remains poorly understood. LMAN1 MCFD2 form complex at the endoplasmic reticulum membrane, recruiting cargo proteins into COPII vesicles for secretion. In this study, we showed deficient mice (with complete germline deficiency) exhibited mild thrombocytopenia, whereas count was entirely...
SEC23 is a core component of the coat protein-complex II (COPII)-coated vesicle, which mediates transport secretory proteins from endoplasmic reticulum (ER) to Golgi 1-3 . Mammals express 2 paralogs for (SEC23A and SEC23B). Though gene duplication dates back >500 million years, both SEC23’s are ~85% identical at amino acid sequence level. In humans, deficiency SEC23A or SEC23B results in cranio-lenticulo-sutural dysplasia 4 congenital dyserythropoietic anemia type (CDAII), respectively 5...