Understanding genetics of aging: Canis familiaris model

描述（由申请方提供）：本研究的长期目标是将犬建立为人类衰老模型，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，有一个自然多样的寿命范围，从中采样。与人类相比，寿命较短，这将允许对年轻队列进行分析，而无需对寿命缩短进行未经证实的估计。家犬是特别有用的遗传研究，由于缺乏品种内的异质性，这是一个问题，往往混淆在人类的连锁分析。很有可能的是，人类的异质现象可以更容易地通过利用具有相似的（如果不是相同的）表型但贡献基因较少的模型来解剖。为此，我们提出了与人类衰老有关的基因座的犬直系同源物的鉴定和遗传作图，特别是人类4号染色体上标记D4 S 1564区域内的基因（Puca，2001）。犬直系同源物的鉴定将允许它们在整合的犬联系-辐射杂交图谱上定位。FISH分析将完成绘图工作，并有助于破译目前缺乏的关于人类4号染色体与犬遗传图谱同源区域的数据，以及定义进化断点。最后，利用犬寡核苷酸微阵列芯片开发基因表达谱将允许延长寿命的狗与那些自然寿命短的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.