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

描述(由申请人提供)：原颗粒是一种广泛表达的、分泌的糖蛋白，最初因其生长因子样特性而被发现，后来被发现为额颞叶痴呆的致病基因，这是一种毁灭性的神经退行性疾病，无法治愈。原颗粒还与其他疾病有关，包括癌症、肥胖症、糖尿病、动脉粥样硬化、关节炎和神经性蜡样脂褐素沉着症。因此，更好地了解原颗粒生物学对人类健康和疾病具有广泛的意义。与多种疾病的联系一致，原颗粒参与了多种生理过程，包括细胞存活、肿瘤细胞生长、血管生成、轴突生长、炎症和胰岛素信号转导。然而，关于原颗粒的生物化学和功能的基本问题仍然没有得到回答。它的生物活性形式是原颗粒还是颗粒(S)？原颗粒的结构如何影响其活性？卵裂是否影响原颗粒的活性？我建议不要把重点放在原颗粒的活性和结构的这些生化方面。使用基于细胞的功能分析，我将定义具有生物活性的原颗粒蛋白区域(S)，并测试活性是否需要将原颗粒蛋白裂解成更小的颗粒蛋白区域。我假设全长的原颗粒蛋白是一种不具有生物活性的前蛋白，被切割的颗粒片段是主要的生物活性物种。此外，我将通过阐明原颗粒二聚化的机制和确定其功能意义来扩展我最近的发现，即原颗粒以同源二聚体的形式存在。最后，我将测试无意义介导的信使核糖核酸衰变抑制作为治疗额颞部痴呆的策略的潜在用途。使用与患者相关的模型，我将测试该策略是否可以恢复截断的原颗粒的表达，从而恢复原颗粒的功能。这些研究的完成将极大地促进我们对原颗粒的活性和生化性质的理解。这些基础知识将为未来旨在了解原颗粒的准确功能的研究提供一个生化框架，并可能阐明原颗粒突变如何导致额颞部痴呆。此外，这些研究将为治疗前颗粒素缺乏形式的额颞叶痴呆提供一种新的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.