Characterization of Atmtm1Awb Congenic Strains

描述（由申请人提供）：约10 - 30%的共济失调-毛细血管扩张（A-T）患者发展为白血病或淋巴瘤。在发病年龄和白血病/淋巴瘤类型方面，患者之间存在相当大的差异。不完全外显率和发病年龄的变化可归因于几个因素。其中包括神经退行性疾病和间质性肺疾病的竞争性死亡率，以及ATM基因突变的等位基因特异性影响。此外，从临床观察和使用Atm敲除小鼠的研究中，有限的证据表明修饰基因可能解释了白血病/淋巴瘤易感性的一些变化。我们将Atmtm1Awb敲除等位基因（Atm-）渐渗到几个近交小鼠品系上，观察了不同品系背景下Atm-/-小鼠的存活率差异。本提案的主要目的是表征这些Atm-/-同源菌株胸腺淋巴瘤的发病率和发病潜伏期，作为鉴定淋巴瘤发生修饰基因的前奏。第二个目的是检测老龄Atm-/-小鼠的神经变性和间质性肺疾病，因为这些临床上重要的表型在现有的Atm敲除小鼠品系中没有重现。公共卫生相关性：共济失调毛细血管扩张（A-T）患者死亡的主要原因是间质性肺疾病和癌症，特别是白血病和淋巴瘤。这个项目旨在描述一种潜在的a - t动物模型的特征，这种模型可以用来确定为什么有些病人会得白血病，而有些人不会。该模型也可用于测试抗间质性肺疾病和A-T患者神经变性的潜在治疗方法。

DESCRIPTION (provided by applicant): About 10 to 30% of ataxia-telangiectasia (A-T) patients develop leukemias or lymphomas. There is considerable interpatient variation in the age of onset and leukemia/lymphoma type. The incomplete penetrance and variable age of onset may be attributable to several factors. These include competing mortality from neurodegeneration and interstitial lung disease, and allele specific effects of ATM gene mutations. Also, there is limited evidence from clinical observations and studies using Atm knockout mice that modifier genes may account for some variation in leukemia/lymphoma susceptibility. We have introgressed the Atmtm1Awb knockout allele (Atm-) onto several inbred murine strains and observed differences in survival between Atm-/- mice on the different strain backgrounds. The primary aim of this proposal is to characterize the incidence and onset latency of thymic lymphoma in these Atm-/- congenic strains as a prelude to identifying lymphomagenesis modifier genes. A secondary aim is to assay aged Atm-/- mice for neurodegeneration and interstitial lung disease, since these clinically important phenotypes are not recapitulated in existing Atm knockout mouse strains. PUBLIC HEALTH RELEVELANCE: The major causes of death in ataxia-telangiectasia (A-T) patients are interstitial lung disease and cancer, specifically leukemias and lymphomas. This project aims to characterize a potential animal model for A-T that can be used to determine why some patients get leukemia and others don't. The model may also be useful for the testing of potential therapies against interstitial lung disease and neurodegeneration in A-T patients.