Mapping Progranulin's Bioactivity: Implications for Disease and Potential Therapies

描述（由申请人提供）：颗粒蛋白前体是一种广泛表达的分泌型糖蛋白，最初因其生长因子样特性而被发现，后来被鉴定为额颞叶痴呆的致病基因，额颞叶痴呆是一种无法治愈的破坏性神经退行性疾病。颗粒蛋白前体还涉及其他疾病，包括癌症、肥胖症、糖尿病、动脉粥样硬化、关节炎和神经元蜡样脂褐质沉积症。因此，更好地了解颗粒蛋白前体生物学对人类健康和疾病具有广泛的意义。与其与多种疾病的联系一致，颗粒蛋白前体参与多种生理过程，包括细胞存活、肿瘤细胞生长、血管形成、神经突生长、炎症和胰岛素信号传导。然而，关于颗粒蛋白前体生物化学和功能的基本问题仍然没有答案。它的生物活性形式是什么-颗粒蛋白前体或颗粒蛋白（S）？颗粒蛋白前体的结构如何影响其活性？卵裂影响颗粒蛋白前体活性吗？我建议把重点放在这些生化方面的颗粒蛋白前体的活性和结构。使用基于细胞的功能测定，我将定义颗粒蛋白前体的生物活性区域，并测试颗粒蛋白前体是否裂解成更小的颗粒蛋白结构域是活性所必需的。我推测，全长颗粒蛋白原是一种前蛋白，不具有生物活性和切割颗粒蛋白片段是主要的生物活性物种。此外，我将通过阐明颗粒蛋白前体二聚化的机制和确定其功能意义来扩展我最近的发现，即颗粒蛋白前体以同源二聚体的形式存在。最后，我将测试无义介导的mRNA衰减抑制作为治疗额颞叶痴呆的治疗策略的潜在效用。使用患者相关的模型，我将测试这种策略是否可以恢复表达截短的颗粒蛋白前体，因此，颗粒蛋白前体的功能。这些研究的完成将大大推进我们对颗粒蛋白前体的活性和生物化学性质的理解。这一基础知识将为未来的研究提供一个生化框架，旨在了解颗粒蛋白前体的确切功能，并可能揭示颗粒蛋白前体突变如何导致额颞叶痴呆。此外，这些研究将提供有关治疗前颗粒蛋白缺乏型额颞叶痴呆的新型治疗方法的潜在效用的初步见解。

DESCRIPTION (provided by applicant): Progranulin is a widely expressed, secreted glycoprotein, originally discovered for its growth factor-like properties, and later identified as causative gene for frontotemporal dementia, a devastating neurodegenerative disease with no cure. Progranulin is also implicated in other diseases including cancer, obesity, diabetes, atherosclerosis, arthritis, and neuronal ceroid lipofuscinosis. Thus, a better understanding of progranulin biology has widespread significance for human health and disease. Consistent with its links to multiple diseases, progranulin participates in a multitude of physiological processes including cell survival, tumor cell growth, vascularization, neurite outgrowth, inflammation and insulin signaling. Yet, fundamental questions regarding progranulin biochemistry and function remain unanswered. What is its bioactive form- progranulin or granulin(s)? How does progranulin's structure affect its activity? Does cleavage affect progranulin activity? I propose t focus on these biochemical aspects of progranulin's activity and structure. Using cell-based functional assays, I will define the region(s) of progranulin which are bioactive and test if cleavage of progranulin into smaller granulin domains is required for activity. I hypothesize that full-length progranulin is a pro-protein which does not possess bioactivity and that the cleaved granulins fragments are the major bioactive species. Additionally, I will extend my recent finding that progranulin exists as homodimers by elucidating the mechanism underlying progranulin dimerization and determining its functional significance. Finally, I will test the potential utilit of nonsense-mediated mRNA decay inhibition as a therapeutic strategy for treating frontotemporal dementia. Using patient-relevant models, I will test if this strategy can restore expression of truncated progranulin and, thus, progranulin function. Completion of these studies will significantly advance our understanding of progranulin's activity and biochemical nature. This fundamental knowledge will provide a biochemical framework for future studies aimed at understanding progranulin's precise function and may shed light on how progranulin mutations cause frontotemporal dementia. Moreover, these studies will provide initial insights about the potential utility of a novel therapeutic approach for treating progranulin-deficient forms of frontotemporal dementia.