Abstract

Background: In humans, measuring the frequency (f) of cells harboring a mutation is possible for a very small number of sentinel genes and historically has been technically difficult. Measuring the mutation rate (<)--which represents the probability of new mutations occurring in a gene per cell division-- has been virtually impossible. Nevertheless, f and Specific Aims (a): to determine whether For aim (a), volunteer subjects in different age groups will be recruited, and For aim (b), using cells from normal older individuals and patients with progeria, the effect on the mutation rate will be determined for three pharmacologic approaches: quenching reactive oxygen species, modulating lamin A using farnesyltransferase inhibitors, and activating SIRT1. Preliminary data:

Public Health Relevance

Narrative: The Department of Veterans'Affairs cares for a large cohort of elderly patients who are prone to cancer because they are elderly. A better understanding of the relationship between ageing and the mutation rate is very much needed to plan studies to prevent cancer in this population. The studies proposed here will help predict at what age intervention to decrease mutations might be required. These studies may also identify drugs that are likely to prevent mutations and cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX000670-01
Application #
7798341
Study Section
Oncology A (ONCA)
Project Start
2009-10-01
Project End
2013-09-30
Budget Start
2009-10-01
Budget End
2010-09-30
Support Year
1
Fiscal Year
2009
Total Cost
Indirect Cost

  Institution

Name
VA Medical Center
Department
Type
DUNS #
070501002
City
New York
State
NY
Country
United States
Zip Code
10010

  Publications

Evensen, Nikki A; Madhusoodhan, P Pallavi; Meyer, Julia et al. (2018) MSH6 haploinsufficiency at relapse contributes to the development of thiopurine resistance in pediatric B-lymphoblastic leukemia. Haematologica 103:830-839
Araten, David J; Zamechek, Leah; Halverson, Gregory (2014) No evidence of hypermutability in red cells from patients with paroxysmal nocturnal hemoglobinuria using the XK gene. Haematologica 99:e142-4
Araten, David J; Krejci, Ondrej; Ditata, Kimberly et al. (2013) The rate of spontaneous mutations in human myeloid cells. Mutat Res 749:49-57
Sugimori, C; Padron, E; Caceres, G et al. (2012) Paroxysmal nocturnal hemoglobinuria and concurrent JAK2(V617F) mutation. Blood Cancer J 2:e63
Araten, David J; Sanders, Katie J; Anscher, Dan et al. (2012) Leukemic blasts with the paroxysmal nocturnal hemoglobinuria phenotype in children with acute lymphoblastic leukemia. Am J Pathol 181:1862-9