新浪登录
腾讯登录Diabetes：PTPN22突变增加患糖尿病风险
| 导读 | 近日，Joslin糖尿病中心科学家正在研究基因在1型糖尿病发展中的作用，与维尔茨堡大学的科学家合作，已经揭示了与1型糖尿病等自身免疫性疾病的相关遗传变异是如何影响自身免疫性疾病的易感性。这一发现刊登在最新一期的<em>Diabetes</em>杂志上。
<!--more-->
最新研究已经确定人类基因组中与自身免疫性疾病的区域，如1型糖尿病相关的基因... |
近日，Joslin糖尿病中心科学家正在研究基因在1型糖尿病发展中的作用，与维尔茨堡大学的科学家合作，已经揭示了与1型糖尿病等自身免疫性疾病的相关遗传变异是如何影响自身免疫性疾病的易感性。这一发现刊登在最新一期的<em>Diabetes</em>杂志上。
<!--more-->
最新研究已经确定人类基因组中与自身免疫性疾病的区域，如1型糖尿病相关的基因区域。研究人员设法了解与各种自身免疫性疾病相关的基因是如何最广泛提高疾病风险的。
这些基因之一是PTPN22，其在调控淋巴细胞（免疫细胞）功能中起重要作用。PTPN22基因变异（或突变）与1型糖尿病和其他一些自身免疫性疾病有关。PTPN22还参与淋巴酪氨酸磷酸酶（LYP）的形成，后者是控制免疫系统中T和B细胞活性的关键蛋白。
PTPN22突变生成具有不同分子结构的LYP。大多数有关PTPN22病变异的研究表明这种变体能提高LYP活动，减少T细胞和B细胞的活性，增加患自身免疫疾病风险。
在免疫细胞发展成熟过称中，免疫细胞活性的较低有助于防止自身免疫性疾病。然而，一项研究对人类和转基因小鼠后分析后发现与1型糖尿病相关的LYP变异却是能降低LYP的活性的。
为了帮助解决冲突的数据，科学家进用独特的动物模型设计实验。使用RNA干扰和慢病毒转基因相结合的技术，科学家们可以在最广泛的1型糖尿病小鼠模型即肥胖性糖尿病小鼠（NOD ）中控制基因的活动。
在这项研究中，研究人员能够轻松地打开和关闭NOD小鼠的PTPN22基因。PTPN22被关闭的小鼠，研究人员发现调节性T细胞活性增加，自身免疫性糖尿病的风险降低。此外，研究数据表明PTPN22是潜在治疗靶点，抑制LYP或许可防止自身免疫疾病。
<img src="http://www.bioon.com/biology/UploadFiles/201211/2012112914382780.gif" alt="" width="115" height="150" border="0" />
<div id="ztload">
<div>
<div>
doi:10.2337/db12-0929
PMC:
PMID:
</div>
<div>
<br/><strong>PTPN22 Silencing in the NOD Model Indicates the Type 1 Diabetes-Associated Allele Is Not a Loss-of-Function Variant</strong><br/>
P. Zheng, S. Kissler.
PTPN22 encodes the lymphoid tyrosine phosphatase (LYP) and is the second strongest non-HLA genetic risk factor for type 1 diabetes. The PTPN22 susceptibility allele generates an LYP variant with an arginine to tryptophan substitution at position 620 (R620W) that has been reported by several studies to impart a gain of function. However, a recent report investigating both human cells and a knockin mouse model containing the R620W homolog suggested that this variation causes faster protein degradation. Whether LYP R620W is a gain- or loss-of-function variant, therefore, remains controversial. To address this issue, we generated transgenic NOD mice (nonobese diabetic) in which Ptpn22 can be inducibly silenced by RNA interference. We found that Ptpn22 silencing in the NOD model replicated many of the phenotypes observed in C57BL/6 Ptpn22 knockout mice, including an increase in regulatory T cells. Notably, loss of Ptpn22 led to phenotypic changes in B cells opposite to those reported for the human susceptibility allele. Furthermore, Ptpn22 knockdown did not increase the risk of autoimmune diabetes but, rather, conferred protection from disease. Overall, to our knowledge, this is the first functional study of Ptpn22 within a model of type 1 diabetes, and the data do not support a loss of function for the PTPN22 disease variant.
<br/>来源：生物谷
</div>
</div>
</div>
<!--more-->
最新研究已经确定人类基因组中与自身免疫性疾病的区域，如1型糖尿病相关的基因区域。研究人员设法了解与各种自身免疫性疾病相关的基因是如何最广泛提高疾病风险的。
这些基因之一是PTPN22，其在调控淋巴细胞（免疫细胞）功能中起重要作用。PTPN22基因变异（或突变）与1型糖尿病和其他一些自身免疫性疾病有关。PTPN22还参与淋巴酪氨酸磷酸酶（LYP）的形成，后者是控制免疫系统中T和B细胞活性的关键蛋白。
PTPN22突变生成具有不同分子结构的LYP。大多数有关PTPN22病变异的研究表明这种变体能提高LYP活动，减少T细胞和B细胞的活性，增加患自身免疫疾病风险。
在免疫细胞发展成熟过称中，免疫细胞活性的较低有助于防止自身免疫性疾病。然而，一项研究对人类和转基因小鼠后分析后发现与1型糖尿病相关的LYP变异却是能降低LYP的活性的。
为了帮助解决冲突的数据，科学家进用独特的动物模型设计实验。使用RNA干扰和慢病毒转基因相结合的技术，科学家们可以在最广泛的1型糖尿病小鼠模型即肥胖性糖尿病小鼠（NOD ）中控制基因的活动。
在这项研究中，研究人员能够轻松地打开和关闭NOD小鼠的PTPN22基因。PTPN22被关闭的小鼠，研究人员发现调节性T细胞活性增加，自身免疫性糖尿病的风险降低。此外，研究数据表明PTPN22是潜在治疗靶点，抑制LYP或许可防止自身免疫疾病。
<img src="http://www.bioon.com/biology/UploadFiles/201211/2012112914382780.gif" alt="" width="115" height="150" border="0" />
<div id="ztload">
<div>
<div>
doi:10.2337/db12-0929
PMC:
PMID:
</div>
<div>
<br/><strong>PTPN22 Silencing in the NOD Model Indicates the Type 1 Diabetes-Associated Allele Is Not a Loss-of-Function Variant</strong><br/>
P. Zheng, S. Kissler.
PTPN22 encodes the lymphoid tyrosine phosphatase (LYP) and is the second strongest non-HLA genetic risk factor for type 1 diabetes. The PTPN22 susceptibility allele generates an LYP variant with an arginine to tryptophan substitution at position 620 (R620W) that has been reported by several studies to impart a gain of function. However, a recent report investigating both human cells and a knockin mouse model containing the R620W homolog suggested that this variation causes faster protein degradation. Whether LYP R620W is a gain- or loss-of-function variant, therefore, remains controversial. To address this issue, we generated transgenic NOD mice (nonobese diabetic) in which Ptpn22 can be inducibly silenced by RNA interference. We found that Ptpn22 silencing in the NOD model replicated many of the phenotypes observed in C57BL/6 Ptpn22 knockout mice, including an increase in regulatory T cells. Notably, loss of Ptpn22 led to phenotypic changes in B cells opposite to those reported for the human susceptibility allele. Furthermore, Ptpn22 knockdown did not increase the risk of autoimmune diabetes but, rather, conferred protection from disease. Overall, to our knowledge, this is the first functional study of Ptpn22 within a model of type 1 diabetes, and the data do not support a loss of function for the PTPN22 disease variant.
<br/>来源：生物谷
</div>
</div>
</div>
还没有人评论，赶快抢个沙发