Pathologic hemorrhage is a major contributor to morbidity and mortality for both the general population as well as individuals with bleeding disorders. While major improvements to human health have been made with blood products and human derived or recombinant coagulation factors, these have limited shelf life and storage conditions, and require intravenous infusion. There are exceedingly few potent and stable conventional pharmaceutical agents for treatment of hemorrhage, and there is a strong need for the identification of new therapeutics and targets. This project will leverage highly innovative technologies, including genome editing nucleases, next generation sequencing, and the zebrafish model to delve into the evolutionary conservation of hemostasis, and use this information to conduct an in vivo high throughput analysis of small molecules and genetic targets for treatment of a hemorrhagic phenotype. In preliminary studies, we have used robust genome editing nucleases (TALENS and CRISPR/Cas) to generate mutations in procoagulant factors. These mutants display bleeding phenotypes and lethality, correlating with data from mammals.
In Specific Aim 1, we will use genome editing nuclease to evaluate combinatorial actions of multiple coagulation factors for suppression of a model of hemorrhage.
In Specific Aim 2 we will perform a high throughput small molecule screen to detect lead compounds for treatment of hemorrhage, and a sensitized ENU mutagenesis suppressor screen to identify potential modifier genes as new therapeutic targets. These studies will discern interactions amongst candidate modifiers as well as perform an unbiased screen for novel therapeutic drugs and target genes. This will lead to potential innovative agents and therapeutic classes for treatment of hemorrhage that could benefit the general population, as well as patients with bleeding disorders.

Public Health Relevance

Public Health Relevance Statement Pathologic hemorrhage is a major contributor to morbidity and mortality in both the general population as well as individuals with bleeding disorders. While major improvements to human health have been made with natural and synthetic blood products and proteins, these have limited shelf life and storage conditions, require intravenous infusion, and there are very few potent and stable conventional therapeutic agents for treatment of hemorrhage. The proposed studies will identify new diagnostics, therapies and therapeutic targets, which will result in broadened treatment options for a diverse array of affected patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL125774-02
Application #
9624803
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Warren, Ronald Q
Project Start
2018-01-15
Project End
2021-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109