Src family kinases: regulation of phosphoinositol-3 kinase signaling and autoimmune disease development.

免疫系统必须能够对无限的病原体做出反应，但同时对自身抗原保持无反应或耐受。对自身抗原耐受性的破坏导致自身免疫。自身免疫性疾病包括70多种慢性疾病，影响西方人口中约1/20的人。提高我们对自身免疫性疾病机制的理解对于设计更成功的治疗方法至关重要。林恩酪氨酸激酶是一种在血细胞中发现的酶。它参与跨细胞膜传递信息以关闭细胞反应。对突变小鼠的研究表明，林恩对维持免疫系统的稳定至关重要。不能产生林恩蛋白的小鼠（Lyn-deficient mice）以及表达活化形式的林恩酶的小鼠（Lyn-up mice）发展具有与人类自身免疫性疾病系统性红斑狼疮（SLE）相似特征的自身免疫性疾病。这些研究表明，林恩是一个重要的严重性基因在自身免疫。这项资助的目的是确定导致自身免疫性疾病的Lyn-dependent信号通路，主要关注脂质激酶通路。我们将使用遗传学和生物化学方法的组合来揭示关键基因和途径。我们相信，对与林恩活性改变相关的分子变化进行分类，将有助于深入了解人类自身免疫性疾病的遗传缺陷或信号扰动。通过这种方式，我们的研究将有助于人类自身免疫性疾病的诊断，并为更特异和有效的治疗发现有用的靶点。

The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of, self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune disease includes more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more successful treatments. The Lyn tyrosine kinase is an enzyme that is found within blood cells. It participates in transmitting information across the cell membrane to turn off cellular responses. Studies in mutant mice have shown that Lyn is critically important for maintaining stability in the immune system. Mice that are unable to make Lyn protein (Lyn-deficient mice) as well as mice that express an activated form of the Lyn enzyme (Lyn-up mice) develop autoimmune disease with characteristics similar to the human autoimmune disease systemic erythematosus (SLE). These studies suggest that Lyn is an important severity gene in autoimmunity. The aim of this grant will be to identify Lyn-dependent signaling pathways that lead to autoimmune disease, with a major focus being on the lipid kinase pathway. We will use a combination of genetic and biochemical approaches to reveal critical genes and pathways. Cataloging the molecular changes related to alterations in Lyn activity will, we believe, provide insight into the genetic defects or signal perturbations underlying human autoimmune diseases. In this way, our study will aid in the diagnosis of human autoimmune diseases and uncover useful targets for more specific and effective treatments.