FVIII (FVIII) is the plasma protein deficient or functionally defective in hemophilia A, an X-chromosome linked bleeding disorder affecting 1/5,000 males. Affected patients experience significant morbidity and mortality related to repeated and/or life-threatening bleeding events. Protein replacement therapy with recombinant-derived FVIII is presently the preferred therapy. However, the cost of recombinant FVIII and the continued problem ofimmunogenicity remain significant problems. The long term goal of the proposed research is to provide fundamental insight into the regulation of FVIII synthesis and secretion with the ultimate goal of developing improved therapies for hemophilia A.
The specific aims of this proposal are to test the following three hypotheses: FVIII secretion is limited by transient aggregation immediately after its translation. We will characterize the requirements for ATP-dependent dissociation of FVIII aggregates. FVIII expression is toxic to cells by activation or ER stress-response signaling kinases. We will determine whether accumulation of FVIII within the ER activates protein kinases to inhibit protein synthesis and induce transcription of genes encoding ER stress proteins. ERGIC-53 is a molecular chaperone that interacts with the B domains or FV (FV) and F VIII and facilitates their transport to the Golgi compartment. We will elucidate the requirement of ERGIC-53 in the transport of FV and FVIII to the Golgi compartment. These studies will identify folding pathways of FVIII, improve FVIII secretion efficiency and limit toxicity associated with FVIII expression. In addition, these studies will identify how deficiency in ERGIC-53 causes combined deficiency of FV and FVIII. They will provide fundamental new insights into FVIII protein synthesis and secretion. The information will be vital to the future development of improved gene therapy protocols for hemophilia A. The ER provides an essential function to promote folding of proteins destined for the cell surface. Elucidating the mechanisms of protein folding, retention, and transport through the ER will have impact on the ability to therapeutically intervene in disease states that are associated with defective protein folding in the ER.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Link, Rebecca P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Ravindran, Rajesh; Loebbermann, Jens; Nakaya, Helder I et al. (2016) The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature 531:523-527
Yang, Liu; Li, Shaohua; Miao, Linqing et al. (2016) Rescue of Glaucomatous Neurodegeneration by Differentially Modulating Neuronal Endoplasmic Reticulum Stress Molecules. J Neurosci 36:5891-903
Wang, Shiyu; Park, Shuin; Kodali, Vamsi K et al. (2015) Identification of protein disulfide isomerase 1 as a key isomerase for disulfide bond formation in apolipoprotein B100. Mol Biol Cell 26:594-604
Kohl, Susanne; Zobor, Ditta; Chiang, Wei-Chieh et al. (2015) Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat Genet 47:757-65
Xi, Y; Garshott, D M; Brownell, A L et al. (2015) Cantharidins induce ER stress and a terminal unfolded protein response in OSCC. J Dent Res 94:320-9
Han, Jaeseok; Song, Benbo; Kim, Jiun et al. (2015) Antioxidants Complement the Requirement for Protein Chaperone Function to Maintain ?-Cell Function and Glucose Homeostasis. Diabetes 64:2892-904
Genereux, Joseph C; Qu, Song; Zhou, Minghai et al. (2015) Unfolded protein response-induced ERdj3 secretion links ER stress to extracellular proteostasis. EMBO J 34:4-19
D'Osualdo, Andrea; Anania, Veronica G; Yu, Kebing et al. (2015) Transcription Factor ATF4 Induces NLRP1 Inflammasome Expression during Endoplasmic Reticulum Stress. PLoS One 10:e0130635
Hassler, Justin R; Scheuner, Donalyn L; Wang, Shiyu et al. (2015) The IRE1?/XBP1s Pathway Is Essential for the Glucose Response and Protection of ? Cells. PLoS Biol 13:e1002277
Zhou, Alex-Xianghua; Wang, Xiaobo; Lin, Chyuan Sheng et al. (2015) C/EBP-Homologous Protein (CHOP) in Vascular Smooth Muscle Cells Regulates Their Proliferation in Aortic Explants and Atherosclerotic Lesions. Circ Res 116:1736-43

Showing the most recent 10 out of 140 publications