Characterization of Atmtm1Awb Congenic Strains

描述(申请人提供)：大约10%到30%的共济失调-毛细血管扩张症(A-T)患者会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，患者之间有相当大的差异。不完全外显和发病年龄可变可能是由几个因素引起的。这些因素包括神经退行性变和间质性肺病的竞争性死亡率，以及ATM基因突变的等位基因特异性影响。此外，来自临床观察和使用ATM基因敲除小鼠的研究表明，修饰基因可能解释了白血病/淋巴瘤易感性的一些变化，这一证据有限。我们将Atmtm1Awb基因敲除等位基因(ATM-)导入到几个近交系小鼠中，并观察到不同品系背景下ATM-/-小鼠的存活率差异。这项建议的主要目的是表征这些ATM-/-同源菌株中胸腺淋巴瘤的发生率和发病潜伏期，作为识别淋巴生成调节因子基因的前奏。第二个目的是检测老年ATM-/-小鼠的神经退行性变和间质性肺疾病，因为这些临床上重要的表型在现有的ATM基因敲除小鼠品系中没有概括。公共卫生报道：共济失调-毛细血管扩张症(A-T)患者的主要死亡原因是间质性肺疾病和癌症，特别是白血病和淋巴瘤。这个项目的目的是描述一种潜在的A-T动物模型，该模型可以用来确定为什么一些患者会患白血病，另一些患者不会。该模型也可能有助于测试A-T患者治疗间质性肺疾病和神经变性的潜在疗法。

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.