Projects Overview
Overview
This Program Project Grant (PPG) aims to address important gaps in knowledge concerning the genetic, molecular and biologic control of von Willebrand factor (VWF) and pathogenesis of von Willebrand disease (VWD). Despite significant advances in the field fundamental scientific questions that have direct translational implications remain unanswered, including the association of VWF levels and bleeding risk, the role of VWF in Factor VIII (FVIII) biology and the mechanisms through which glycans affect VWF life cycle, including changes associated with the aging process. This PPG consists of 4 projects and 3 cores that all focus on VWF and mechanisms influencing its genetic regulation, expression, dysfunction, increased clearance, interactions with FVIII and the role of carbohydrate modification in VWF biology. While this is a new PPG application, this program leverages the synergistic interactions of a group of collaborative scientists and has access to tens of thousands of samples and extensive biodata from the pre-existing PPG, the Zimmerman Program.
Leader: PhD Brooke Sadler
Aim of Project 1 is to focus on resolving, by identifying common and rare variants, including complex loci, the condition called low von Willebrand factor; the 20-25% increase in VWF levels seen in individuals from African Ancestry; and the increase in VWF levels observed with aging. Cohorts of subjects with low VWF, with no sequence variants in VWF will undergo whole genome and long read sequencing. Whole genome sequencing of multiple multiethnic cohorts will allow for admixture studies that will leverage the power of trans-ethnic fine mapping and haplotype association.
Leader: Dr. Jorge Di Paola
Aim of Project 2 is to generate a detailed molecular landscape of low VWF and VWD type 1, resolve the complex genetic and biological architecture that underlies these two disorders, and generate new prediction models for disease risk. This will be done by generating and analyzing human relevant tissues and cell types for VWF (plasma, endothelial cells, platelets) and multi-omics data (genetic, transcriptomic, epigenomic, proteomic, metabolomics and lipidomic) in thousands samples from patients, relatives and controls; as well as by performing longitudinal analyses on patients’ samples to study the effect of aging on VWF levels.
Leader: Dr. David Lillicrap
Aim of Project 3 is to advance knowledge of the genomic and environmental influences that regulate the expression of VWF. These studies will use spatial transcriptomic analysis to characterize the endothelial subtypes and anatomic niches of cells expressing VWF and/or FVIII. Studies aimed at characterizing the influence of non-coding sequence variation on VWF transcriptional activity will utilize a range of strategies including integration of genomic data from large populations with low or high VWF. Lastly, the mechanistic basis for the age-dependent increase in VWF will be investigated.
Leader: O'Donnell, James
Aim of Project 4 is to identify the specific contributions of N- and O-glycans in VWF biosynthesis including trafficking, storage and secretion; their role in VWF activation and function and the potential relationship between activation and clearance; and the effect that these deficiencies have in patients with low VWF and type 1 VWD. This will be done with a combination of cellular and animal models as well as plasma samples from deeply phenotyped VWD patients in the Zimmerman biorepository.