Characterization of Atmtm1Awb Congenic Strains

Atmtm1Awb 同源菌株的表征

• 批准号: 7512940
• 负责人: Michael M. Weil
• 金额: $ 7.35万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7512940
• 关键词: ATM Gene Mutation; Accounting; Age; Age of Onset; Age-Months; Alleles; Animal Model; Ataxia Telangiectasia; BALB/cByJ Mouse; Biological Assay; C57BL/6 Mouse; Cause of Death; Cells; Characteristics; Clinical; Congenic Strain; DNA; Data; Development; Engineering; Event; Failure; Future; Genes; Genetic; Histopathology; Immunohistochemistry; Inbred Strain; Incidence; Injury; Interstitial Lung Diseases; Knock-out; Knockout Mice; Lead; Lesion; Life; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Methods; Modeling; Molecular; Monitor; Mouse Strains; Mus; Nerve Degeneration; Pathology; Patients; Penetrance; Phenotype; Play; Predisposition; Public Health; Role; Stress; Survivors; Testing; Therapeutic Intervention; Thymic Lymphoma; Time; Variant; aged; early onset; gene cloning; leukemia; leukemia/lymphoma; lung injury; mortality; neuropathology; prevent; respiratory

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.

描述（由申请人提供）：约10 - 30%的共济失调-毛细血管扩张症（A-T）患者发生白血病或淋巴瘤。在发病年龄和白血病/淋巴瘤类型方面存在相当大的患者间差异。不完全性痴呆和发病年龄的变化可能归因于几个因素。这些包括神经变性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效应。此外，从临床观察和使用Atm基因敲除小鼠的研究中获得的证据有限，这些证据表明修饰基因可能导致白血病/淋巴瘤易感性的一些变化。我们已经将Atmtm 1Awb敲除等位基因（Atm-）渗入到几种近交系小鼠品系中，并观察到不同品系背景下Atm-/-小鼠之间的存活差异。本提案的主要目的是描述这些Atm-/-同源株中胸腺淋巴瘤的发病率和发病潜伏期，作为识别淋巴瘤发生修饰基因的前奏。第二个目的是测定老年Atm-/-小鼠的神经变性和间质性肺病，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-毛细血管扩张症（A-T）患者的主要死亡原因是间质性肺病和癌症，特别是白血病和淋巴瘤。该项目旨在描述A-T的潜在动物模型，可用于确定为什么有些患者患有白血病而另一些患者没有。该模型也可用于测试针对A-T患者中的间质性肺病和神经变性的潜在疗法。