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）：大约10％至30％的共济失调 - 链昔切（A-T）患者患有白血病或淋巴瘤。发病年龄和白血病/淋巴瘤类型的年龄较大。不完整的外渗和发病年龄可变的可能归因于几个因素。这些包括来自神经变性和间质性肺部疾病的竞争死亡率，以及ATM基因突变的特异性作用。此外，从临床观察结果和使用ATM基因敲除小鼠进行研究的证据中，修饰剂基因可能会解释白血病/淋巴瘤敏感性的某些变化。我们已经将ATMTM1AWB敲除等位基因（ATM-）渗入了几种近交鼠菌株，并观察到在不同应变背景上ATM - / - 小鼠之间的存活率差异。该提案的主要目的是表征这些ATM - / - 先天性菌株中胸腺淋巴瘤的发病率和发作潜伏期，是鉴定淋巴细胞修饰基因基因的序言。次要的目的是分析陈年的ATM - / - 小鼠用于神经变性和间质性肺疾病，因为在现有的ATM敲除小鼠菌株中未概括这些临床上重要的表型。公共卫生伴侣：共济失调 - 链昔切氏症（A-T）患者的主要死亡原因是间质肺部疾病和癌症，特别是白血病和淋巴瘤。该项目旨在表征A-T的潜在动物模型，该模型可用于确定某些患者为什么患有白血病而其他患者没有使用。该模型也可能对A-T患者中针对间质性肺部疾病和神经退行性的潜在疗法进行测试。