Activation and regulation of the neural stem cell-expressed receptor GPR56

描述(申请人提供)：孤儿G蛋白偶联受体GPR56在神经干细胞(NSCs)中高度表达，GPR56突变导致人类大脑发育障碍。GPR56在NSC功能中发挥的关键作用使其成为可能具有高度选择性NSC调节作用的治疗药物的靶点。然而，目前对GPR56的基本性质知之甚少。治疗学对GPR56的特异性靶向需要更全面地了解控制受体激活、调节和定位的分子机制。因此，我们将研究GPR56的激活机制，特别是N末端(NT)的脱落是否参与受体激活的问题。我们还将研究控制GPR56-NT脱落的因素，以及NT结合肽是否会影响受体的激活。此外，我们将评估已经在初步工作中确定的受体的细胞质结合伙伴对GPR56活性的调节，包括β-拦阻素和PDZ支架。最后，我们将研究控制GPR56在神经干细胞和其他细胞类型中定位的因素，特别强调确定受体靶向纤毛的重要性。除了提供关于GPR56基本特性的见解外，这些研究还将为将GPR56作为一种选择性调节神经干细胞功能的手段用于治疗各种神经发育和神经退行性疾病奠定基础。

DESCRIPTION (provided by applicant): The orphan G protein-coupled receptor GPR56 is highly-expressed in neural stem cells (NSCs), and mutations in GPR56 cause disordered brain development in humans. The key role that GPR56 plays in NSC function makes it an attractive target for therapeutics that might be capable of highly-selective NSC modulation. However, little is currently known about the fundamental properties of GPR56. The specific targeting of GPR56 by therapeutics will require a more comprehensive understanding of the molecular mechanisms controlling receptor activation, regulation and localization. We will therefore study the mechanism of activation for GPR56, examining in particular the issue of whether shedding of the N-terminus (NT) is involved in receptor activation. We will also study the factors controlling GPR56-NT shedding, as well as whether receptor activation can be influenced by NT-binding peptides. Furthermore, we will assess the regulation of GPR56 activity by cytoplasmic binding partners of the receptor that have been identified in preliminary work, including beta-arrestins and PDZ scaffolds. Finally, we will study the factors controlling GPR56 localization in NSCs and other cell types, with a particular emphasis on determining the importance of receptor targeting to cilia. In addition to providing insights about the fundamental properties of GPR56, these studies will lay the groundwork for targeting GPR56 as a means of selectively modulating NSC function in the treatment of various neurodevelopmental and neurodegenerative diseases.