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

描述（由申请人提供）：孤儿G蛋白偶联受体GPR56在神经干细胞（NSCs）中高表达，GPR56的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具有高选择性NSC调节能力的治疗靶点。然而，目前对GPR56的基本性质知之甚少。治疗药物对GPR56的特异性靶向，需要对控制受体激活、调控和定位的分子机制有更全面的了解。因此，我们将研究GPR56的激活机制，特别是研究n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激活。此外，我们将评估GPR56受体的细胞质结合伙伴（包括β -阻滞蛋白和PDZ支架）对GPR56活性的调节作用。最后，我们将研究控制GPR56在NSCs和其他细胞类型中的定位的因素，特别强调确定受体靶向纤毛的重要性。除了提供关于GPR56的基本特性的见解外，这些研究将为靶向GPR56作为选择性调节NSC功能治疗各种神经发育和神经退行性疾病的手段奠定基础。

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. PUBLIC HEALTH RELEVANCE: The modulation of neural stem cells is a promising therapeutic approach in the treatment of various neurodevelopmental and neurodegenerative diseases. The orphan G protein-coupled receptor GPR56 is highly-expressed in neural stem cells and is therefore an attractive target for therapeutics that might be capable of highly-selective modulation of neural stem cell function. The proposed project will study GPR56 activation and regulation to lay the groundwork for potential therapeutic targeting of this receptor, which is expressed in neural stem cells.