Translational study of the genetics of systemic autoimmunity based on mouse mutagenesis

基于小鼠诱变的系统自身免疫遗传学的转化研究

• 批准号: nhmrc : 316914
• 负责人: Prof Carola Vinuesa
• 金额: $ 34.57万
• 依托单位: Australian National University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/translational-study-genetics-mouse-mutagenesis/94895
• 关键词: Translational; study; genetics; systemic; autoimmunity

Lupus is the prototypic autoimmune disease. It is characterised by inflammation that can damage virtually any organ in the body. This inflammation is the outcome of a complex interplay between the environment and genetic predisposition, resulting in production of antibodies against components of normal tissue. Better characterisation of the genetic basis of lupus is a priority because it is the single best path towards a clearer understanding of the mechanism of this debilitating disease, and ultimately, new therapeutic options. Strategies used to identify the genetic basis of human disease fall into two categories. The first involves gathering genetic information from families with more than one affected member, which is then compared with genetic information from unaffected people. This can identify genetic regions likely to contain disease-causing genes, but so far, this approach has met with limited success in lupus. Although regions of the genome that harbour disease-associated genes have been found, few actual disease causing genes have been confirmed. The second approach begins with known genes that might plausibly cause the disease, based on prior knowledge then tests are performed to see whether particular variants of these genes are more common in patients than in healthy controls. Obviously this approach is usually biased towards investigation of candidate genes that are already well-characterised. In this project, we will combine information obtained from a large-scale mouse-based programme in which genetic changes that cause features of lupus are generated randomly. In other words, there is an unbiased search for candidate genes, which should lead to the discovery of new disease pathways. Since the mouse and human immune systems are remarkably similar, genetic abnormalities that cause features of lupus in mice are highly likely to be informative about the genetic basis of human lupus, a hypothesis we will test with genetic studies in humans with lupus.

狼疮是典型的自身免疫性疾病。它的特点是炎症，几乎可以损害身体的任何器官。这种炎症是环境和遗传倾向之间复杂相互作用的结果，导致产生针对正常组织成分的抗体。更好地表征狼疮的遗传基础是当务之急，因为这是更清楚地了解这种使人衰弱的疾病的机制并最终找到新的治疗选择的唯一最佳途径。用于识别人类疾病遗传基础的策略分为两类。第一个涉及从有不止一名受影响成员的家庭收集遗传信息，然后将其与未受影响的人的遗传信息进行比较。这可以识别可能含有致病基因的遗传区域，但到目前为止，这种方法在狼疮方面取得的成功有限。尽管已经发现了含有疾病相关基因的基因组区域，但很少有真正的致病基因得到证实。第二种方法从可能导致疾病的已知基因开始，基于先验知识，然后进行测试，看看这些基因的特定变异在患者中是否比健康对照更常见。显然，这种方法通常偏向于研究已经充分表征的候选基因。在这个项目中，我们将结合从大规模小鼠程序中获得的信息，其中导致狼疮特征的遗传变化是随机生成的。换句话说，对候选基因进行公正的搜索，这应该会导致新的疾病途径的发现。由于小鼠和人类的免疫系统非常相似，导致小鼠狼疮特征的遗传异常很可能提供有关人类狼疮的遗传基础的信息，我们将通过对患有狼疮的人类进行遗传研究来检验这一假设。