We have generated much evidence of both a """"""""direct"""""""" and an """"""""indirect"""""""" nature that the major histocompatibility complex (MHC) influences the aging rate, and some evidence that these effects map to the D and possibly K-A regions of H-2 in mice.
Aim now is to carry forward studies of the relation of the MHC to aging by making transgenic Mus with genes cloned from the MHC of the long-lived (7-8 year) rodent Peromyscus leucopus. Genes from the D-end-like segment of Peromyscus MHC will utilized, including class I genes, TNF, and gene sequences from the same region whose possible functions are not yet specified but may relate to """"""""non- immune"""""""" aspects of the MHC. The peromyscus-> Mus transgenics will be studied for Peromyscus MHC gene and gene product expression and function by neurological technics (immunoprecipitation, flow cytometry, restriction in cytotoxicity), for reproductive senescence, life span and diseases (especially tumor incidences), mRNA levels in several organs for SOD, catalase, mixed function oxidases, class I and II antigens, and tumor necrosis factor (all of which are known to be related to both aging and to the MHC), and repair of DNA adducts following injection of benzo (a)pyrene-trans-7,8-diol, which pilot studies suggests are also both age and MHC related. Further inbreeding of Peromyscus and serologic and molecular genetic studies of Peromyscus MHC will also be done, as adjunct to the above studies.
| Crew, M D; Effros, R B; Walford, R L et al. (1998) Transgenic mice expressing a truncated Peromyscus leucopus TNF-alpha gene manifest an arthritis resembling ankylosing spondylitis. J Interferon Cytokine Res 18:219-25 |
| Crew, M D; Filipowsky, M E (1992) Sequence of the tumor necrosis factor/cachectin (TNF) gene from Peromyscus leucopus (family Cricetidae). Immunogenetics 35:351-3 |
| Crew, M D; Filipowsky, M E; Neshat, M S et al. (1991) Transmembrane domain length variation in the evolution of major histocompatibility complex class I genes. Proc Natl Acad Sci U S A 88:4666-70 |
| Epstein, C J; Berger, C N; Carlson, E J et al. (1990) Models for Down syndrome: chromosome 21-specific genes in mice. Prog Clin Biol Res 360:215-32 |
