The long term objectives of this proposal are to study the interaction of the effect of several genes and environmental factors on life span and to demonstrate that the interactions between these genes are as important in conferring longer life span as the presence of individual genes. We will (a) study the role of one genetic region (Hb-2) in life span using congenic strains of mice. Three strains will be used: B10 (H-2b); B10.D2/nSn (H-2d) and B10.BR (H-2k) and hybrids among them to rank higher survival with heterozygosity of H-2. The study will also test whether subregions of H-2 located near the K end or the D end are important. For the effect of the K end we will compare (B10.A x B10.D2/nSn)F1. We will (b) study the role of several genetic regions in life span using hybrids and recombinant lines, especially a segment of Chromosome 17 carrying H-2, a segment of Chromosome 4 carrying b and sex. These segments will be investigated using backcross mice (C57BL/6xDBA/2)F1 x DBA/2, recombinant lines; and F2 hybrids produced by mating (C57BL/6 x DBA/2)F1 mice. Using backcross mice we will attempt to confirm the role of the segment of Chromosome 4 carrying b interacting with sex in life span and finding that the more heterozygosity, the longer the life span. Also, the role of these interactions and the b locus in immune vigor and in development of non-lymphoma solid tumors will be studied. The genetic interaction between heterozygosity at one or more loci and homozygosity at a second or more loci affecting life span will be investigated using the F2d hybrid mice. For example, the interaction between H-2b/H-2b, H-2b/H-2d, H-2d/H-2d will be studied with respect to MUP-1a/MUP-1a, MUP-1a/MUP-1b and MUP-1b/MUP-1b and sex because the MUP-1 is a genetic marker of the segment of Chromosome 4 carrying b. We will also determine if other genetic systems (homozygous or heterozygous) in addition to H-2, MUP-1 or sex influence life span (Idh-1, Gpd-1, Gpi-1, Hbb,Mod-1, esterase D and C8). On the other hand, the recombinant lines between C57BL/6 and DBA/2 will compare the number of dominant alleles derived from such chromosomes which will produce an effect on life span. Our studies will attempt to relate genotypes to disease patterns associated with aging and immune disturbances. Immune deficiencies and diseases associated with some genotypes in mice may help future attempts to identify similar relationships in man.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG002329-09
Application #
3114401
Study Section
Immunobiology Study Section (IMB)
Project Start
1980-04-01
Project End
1990-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
9
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
Dubey, D P; Husain, Z; Levitan, E et al. (2000) The MHC influences NK and NKT cell functions associated with immune abnormalities and lifespan. Mech Ageing Dev 113:117-34
de Haan, G; Gelman, R; Watson, A et al. (1998) A putative gene causes variability in lifespan among genotypically identical mice. Nat Genet 19:114-6
Weber, G F; Mirza, N M; Yunis, E J et al. (1997) Localization and treatment of an oxidation-sensitive defect within the TCR-coupled signalling pathway that is associated with normal and premature immunologic aging. Growth Dev Aging 61:191-207
Mikael, N; Mirza, N M; Zaharian, B I et al. (1994) Genetic control of the decline of natural killer cell activity in aging mice. Growth Dev Aging 58:3-12
Dubey, D P; Mirza, N M; Zaharian, B I et al. (1993) Role of a genetic region on chromosome 4 in the regulation of natural killer cell activity in mice. Eur J Immunogenet 20:381-9
Yunis, E J; Salazar, M (1993) Genetics of life span in mice. Genetica 91:211-23
Gelman, R; Watson, A; Yunis, E et al. (1990) Genetics of survival in mice: subregions of the major histocompatibility complex. Genetics 125:167-74
Gelman, R; Watson, A; Bronson, R et al. (1988) Murine chromosomal regions correlated with longevity. Genetics 118:693-704
Sanchez de la Pena, S; Halberg, E; Halberg, F et al. (1986) Chronomodulatory effect of cyclosporine upon survival of DBA mice with L1210 leukemia. Chronobiologia 13:129-35
Anderson, D J; Watson, A L; Yunis, E J (1985) Environmental and genetic factors that influence immunity and longevity in mice. Basic Life Sci 35:231-40