Understanding genetics of aging: Canis familiaris model

描述(申请人提供)：这项研究的长期目标是建立犬类作为人类衰老的模型，这将有助于阐明与衰老相关的机制，原因有几个。在物种内部，有一个天然的多样化的寿命范围，以供采样。与人类相比，寿命很短，这将允许对年轻队列进行分析，而不会对寿命缩短做出未经证实的估计。家犬对遗传研究特别有用，因为缺乏品种内的异质性，这是一个经常混淆人类连锁分析的问题。利用一个表型相似但作用基因较少的模型，很有可能更容易剖析人类中的异质性现象。为此，我们提出了与人类衰老有关的犬类基因座的同源基因的鉴定和遗传作图，特别是人类4号染色体上标记D4S 1564区域内的基因(Puca，2001)。犬类同源基因的鉴定将使它们能够在整合的犬类连锁-辐射杂交图谱上进行定位。FISH分析将完成作图工作，并有助于破译目前缺乏的关于人类4号染色体与犬类遗传图谱同源区域的数据，以及确定进化断裂点。最后，利用犬类寡核苷酸微阵列芯片开发基因表达谱，将允许长寿狗与自然短寿狗之间的基因表达比较。

DESCRIPTION (provided by applicant): The long-term objective of this research is to establish the canine as a model of human aging, which would be useful for the elucidation of mechanisms associated with aging for several reasons. Within the species, there is a naturally diverse range of life span from which to sample. Compared to the human, life span is short which will allow analysis of a young cohort without making unconfirmed estimates of reduced life span. Canis familiaris is particularly useful for genetic studies due to a lack of intrabreed heterogeneity, which is a problem often confounding linkage analyses in the human. It is quite possible that heterogeneous phenomena in the human can be more easily dissected by utilizing a model with similar, if not identical phenotype, yet fewer contributing genes. To this end, we propose the identification and genetic mapping of the canine orthologs of loci implicated in human aging, specifically genes within the region of marker D4S 1564 on human chromosome 4 (Puca, 2001). Identification of canine orthologs will allow their positioning on the integrated canine linkage-radiation hybrid map. FISH analysis will complete the mapping efforts and help to decipher the current paucity of data concerning homologous regions of human chromosome 4 to the Canine genetic map as well as define evolutionary breakpoints. Lastly, development of gene expression profiles utilizing canine oligo microarray chips will allow gene expression comparisons between dogs living extended lives verses those having naturally short life spans.