Function of SHP

孤儿受体SHP是核超家族中一个不寻常的成员，它缺乏DNA结合域。它与许多其他超家族成员在功能上相互作用，包括传统的受体和孤儿。它通常会抑制反式激活，但在特定情况下可以起刺激作用。最近，令人兴奋的结果表明，一组罕见的日本青年成熟起病糖尿病患者(MODY)是SHP基因突变的杂合子，这为SHP的潜在功能提供了深入的见解。特别是，由于已知的五个MODY基因之一编码孤儿受体HNF4，而HNF4是SHP的特异性抑制靶点，因此假设SHP与HNF4或其他潜在的转录因子一起作用于胰岛β细胞调节正常的葡萄糖反应。更广泛地说，HNF4和其他潜在的小水电靶标具有深远的重要发育功能，假设完全丧失小水电功能也将对发育产生重要后果。为了检验这些假说，本文提出了三个具体目标。第一个是详细研究SHP和HNF4之间的相互作用，并确定SHP是否也与其他三个MODY转录因子在功能上相互作用。二是确定SHP功能丧失在内胚层发育的拟胚体模型中的后果，特别是它对HNF4/HNF1调控体系的影响。第三种是通过敲入β-半乳糖苷酶基因来灭活小鼠的SHP基因，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是积极的还是消极的。这些研究将为SHP在代谢和发育调节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.