Systemic Lupus Erythematosus (SLE) is an autoimmune disease of unknown etiology. There is currently no cure for this disease that effects substantial numbers of Americans and predominantly females of African-American ancestry. Recent research from our laboratory has provided evidence that aberrant base excision repair leads to the development of lupus in a mouse model. Previous work has shown that the repair of breaks in DNA is compromised in small subsets of lupus patients. In combination, these studies point to a role for aberrant DNA repair in the development of SLE. However, little is known about the genetic basis, and specifically whether germline mutations in DNA repair genes are linked to SLE in patients. In collaboration with members of the Lupus Consortium we have identified a genetic variant (GV) in the PARP1 gene that is associated with SLE. PARP1 encodes PolyADP Ribose Polymerase, which has many cellular roles with the most well characterized being in DNA repair. The GV we have discovered is within an exon of PARP1 and is predicted to lead to expression of a compromised PARP1 protein that may lead to aberrant DNA repair and the development of SLE. The long-term goal of the proposed research is to determine if aberrant DNA repair leads to the development of SLE. The focus of this exploratory project is to test the hypothesis that the PARP1 GV has potential to lead to the development of lupus.
The Specific Aims of the application are 1) To test the hypothesis that mice harboring the PARP1 GV develop lupus and 2) To test the hypothesis that the PARP1 SNP we have identified as being linked to SLE in humans results in compromised DNA repair. To achieve these aims we will generate mice harboring the PARP1 GV and characterize the development of lupus. We will also characterize this variant in tissue culture cells for its ability to participate in DNA rpair and characterize the lymphocytes of individuals with the PARP1 variant to determine if they have compromised DNA repair. This exploratory project will provide a rigorous test of our hypothesis and has the potential to provide mechanistic insights regarding the link between aberrant DNA repair and lupus.

Public Health Relevance

Many Americans have lupus and there is very little known about the etiology of the disease. Lupus has no cure. Our research suggests that people with a mutation in a specific DNA repair gene might be predisposed to SLE. We will characterize this genetic mutation in a mouse model and in cells to determine if it is linked to development of lupus. Our work is significant because it will provide biomarkers for SLE and also we will learn how mutations in DNA repair genes result in lupus. Our work may provide knowledge that can lead to more effective treatment for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI124055-01
Application #
9092164
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Esch, Thomas R
Project Start
2016-04-01
Project End
2018-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Yale University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code