GENETIC CELLULAR AND MOLECULAR STUDIES OF FAS IN SLE

描述（改编自研究者摘要）：SLE是一种 不同的临床、血清学和病理学特征。 多样性是 可能是由遗传的不同组合， 易感基因，可能与环境因素相结合。 具有lpr和gld表型的小鼠长期以来被认为是 SLE。 最近，Fas和Fas配体基因的功能缺失突变 已经被发现是造成这种表型的原因。 上一次融资 我们和其他人已经了解了Fas基因的突变是如何发生的， 凋亡途径导致小鼠自身免疫。 除了Fas途径， 突变，背景基因对临床表达有显着影响， 不同品系小鼠的自身免疫性。 1967年在康奈尔大学首次描述了具有Ipr表型的人类 医学中心 我们已经积累了10个这样的家庭，其中一些家庭 血统 Fas突变个体的表型范围为 临床上无症状至完全发展的SLE。 这个项目的主要目标是 是为了找出额外的修饰基因， 人类狼疮样疾病的表达。 对Fas突变家族的初步研究表明， 许多具有相对较强影响的遗传因素决定疾病 表情 Fas介导的细胞凋亡（FMA）在肿瘤细胞中的功能分析 CSS先证者的家庭已经表明，额外的遗传缺陷 在于凋亡途径。 目的1A将确定家庭成员是否有基因异常 或近端Fas凋亡途径中的蛋白质（FADD、FLICE和 半胱天冬酶）。 目的IB将确定是否替代凋亡途径 如TNF、DR3、DR4在家族成员中受损。 目的2将检验疾病的临床表现需要 杂合Fas突变与第二基因的相互作用。 我们将 试图通过连锁分析和关联来定位第二个基因 问题研究 目标3将检查目标1和目标2中确定的相同遗传缺陷是否存在。 2例发生于SLE患者。

DESCRIPTION (Adapted from Investigator's abstract): SLE is a disease of diverse clinical, serologic and pathologic features. The diversity is likely explained by the inheritance of different combinations of susceptibility genes, possibly in combination with environmental factors. Mice with the lpr and gld phenotype have long been considered a model for SLE. Recently, loss of function mutations in the Fas and Fas ligand genes have been found to be responsible for the phenotype. Over the last funding period, we and others, have gained understanding in how mutations in the Fas apoptotic pathway lead to autoimmunity in mice. In addition to Fas pathway mutations, background genes have a striking effect on clinical expression of autoimmunity in different strains of mice. Humans with the Ipr phenotype were first described in 1967 at the Cornell Medical Center. We have accumulated 10 such families, some with extended pedigrees. The phenotype in individuals with Fas mutations ranges from clinically asymptomatic to full blown SLE. The major goal of this project is to is to identify the additional modifier genes responsible for expression of lupus-like disease in humans. Preliminary studies of families with Fas mutations suggest that a small number of genetic factors with relatively strong effect determine disease expression. Functional analysis of Fas-mediated apoptosis (FMA) in the families of CSS probands have suggested that the additional genetic defect lies in the apoptotic pathway. Aim 1A will determine whether family members have abnormalities in the genes or the proteins in the proximal Fas apoptosis pathway (FADD, FLICE and caspases). Aim IB will determine whether alternative apoptosis pathways such as TNF, DR3, DR4 are impaired in family members. Aim 2 will test the hypothesis that clinical expression of disease requires the interaction of a heterozygous Fas mutation with a second gene. We will attempt to localize the second gene by linkage analysis and by association studies. Aim 3 will examine whether the same genetic defects identified in Aims 1 and 2 occur in patients with SLE.