Function of SHP

孤儿受体SHP是核超家族中不寻常的成员，缺乏DNA结合结构域。它与许多其他超家族成员相互作用，包括传统受体和孤儿。它通常抑制交易激活，但在特定情况下可能具有刺激作用。最近令人兴奋的结果表明，一组不寻常的日本青年糖尿病（MODY）患者是SHP基因突变的杂合型，这为SHP的潜在功能提供了新的见解。特别是由于已知的五个MODY基因之一编码孤儿受体HNF4，这是SHP的特异性抑制靶点，因此假设SHP与HNF4或潜在的其他转录因子一起作用，调节胰腺β细胞的正常葡萄糖反应。更广泛地说，HNF4和其他潜在的SHP靶点具有非常重要的发育功能，并且假设SHP功能的完全丧失也将对发育产生重要影响。本文提出了三个具体目标来检验这些假设。首先是详细描述SHP与HNF4之间的相互作用，并确定SHP是否也与其他三种MODY转录因子在功能上相互作用。二是确定SHP功能丧失对内胚层发育胚胎体模型的影响，特别是其对HNF4/HNF1调控层级的影响。第三种方法是通过敲入β -半乳糖苷酶基因来使小鼠体内的SHP基因失活，并使用一种新的转基因活性陷阱来确定SHP在胰腺和其他组织中的作用是积极的还是消极的。这些研究将为SHP在代谢和发育调控途径中的作用提供新的见解。

The orphan receptor SHP is an unusual member of the nuclear superfamily that lacks a DNA binding domain. It interacts functionally with many other superfamily members, including both conventional receptors and orphans. It generally inhibits transactivation, but can be stimulatory in specific circumstances. Insight into the potential function of SHP was recently provided by exciting results demonstrating that an unusual group of Japanese patients with mature onset diabetes of the young (MODY) are heterozygous for SHP gene mutations. Particularly since one of the five known MODY genes encodes the orphan receptor HNF4, which a specific inhibitory target of SHP, it is hypothesized that SHP acts with HNF4 or potentially other transcription factors to regulate the normal glucose response of pancreatic beta cells. More broadly, HNF4 and other potential SHP targets have profoundly important developmental functions, and it is hypothesized that complete loss of SHP function will also have important consequences for development. Three specific aims are proposed to test these hypotheses. The first is to characterize in detail the interaction between SHP and HNF4, and to determine whether SHP also interactions functionally with the three other MODY transcription factors. The second is to determine the consequences of the loss of SHP function in the embryoid body model of endoderm development, particularly its effects on the HNF4/HNF1 regulatory hierarchy. The third is to inactive the SHP gene in mice by knocking in the beta-galactosidase gene, and also to determine whether SHP acts positively or negatively in the pancreas and other tissues using a novel transgenic activity trap. These studies will provide novel insights into the role of SHP in both metabolic and developmental regulatory pathways.