Diversity Supplement - Progranulin, Prosaposin and Lipid Biology in FTD

多样性补充 - FTD 中的颗粒体蛋白前体、前塞波辛和脂质生物学

• 批准号: 10734455
• 负责人: Aimee Kao
• 金额: $ 24.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734455
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Apoptosis; Biology; Caenorhabditis elegans; Cathepsins; Cell Death; Complex; Data; Dementia; Development; Disease; Disulfides; Event; Exhibits; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Genetic; Glycoproteins; Goals; Health; Homeostasis; Human; Impairment; Individual; Inflammation; Knowledge; Length; Life; Link; Lipids; Lysosomes; Mediating; Membrane; Metabolism; Mission; Modeling; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organelles; Outcome; PGRN gene; Pathogenesis; Pathway interactions; Peptide Hydrolases; Peptides; Play; Population; Process; Production; Proteins; Public Health; Regulation; Research; Role; Saposins; Signal Transduction; Sphingolipids; Stress; System; Tissues; Translating; United States National Institutes of Health; Work; biological adaptation to stress; burden of illness; granulin; insight; lipid metabolism; loss of function mutation; neuropathology; new therapeutic target; pleiotropism; protein TDP-43; protein metabolism; proteostasis; public health relevance; targeted treatment; trafficking

PROJECT SUMMARY Loss-of-function mutations in the progranulin gene (Pgrn haploinsufficiency) cause genetic forms of FTLD with TDP-43 inclusions. The PGRN protein and its bioactive cleavage fragments, the “granulins,” directly modulate activity of the lysosomal protease cathepsin D (CTSD). PGRN traffics to the lysosome as a heterodimer with prosaposin (PSAP). PSAP regulates the levels of sphingolipids, an important class of lipids with roles in intracellular signaling, membrane trafficking and apoptosis. The specific effects of Pgrn haploinsufficiency on protease biology, sphingolipid metabolism and how PGRN and PSAP coordinately regulate protein and lipid homeostasis remain largely unaddressed. We aim to fill these major gaps in knowledge by delineating the complex, downstream effects of PGRN and its cleavage products on lysosomal function. Our long-term goal is to understand how aging and disease- associated lysosomal dysfunction promote neurodegenerative disease. In this application, our overall objective is to determine how Pgrn haploinsufficiency impacts downstream processes such as protease and sphingolipidase activity, TDP-43 and sphingolipid breakdown, and overall protein and lipid homeostasis. Our central hypothesis is that Pgrn haploinsufficiency, via modulation of CTSD activity, confers a “double hit” on protein and lipid metabolism, which impairs both TDP-43 and sphingolipid degradation, ultimately leading to negative downstream consequences on lysosomal function and cellular health. The rationale for our work is that by understanding how PGRN, PSAP and their cleavage products regulate protein and lipid metabolism, we will gain key insights into the mechanisms of neurodegenerative disease pathophysiology. Thus, we propose the following specific aims: 1) Determine how PGRN and its cleavage products affect CTSD-mediated TDP-43 breakdown and protein homeostasis; 2) Understand the impact that PGRN and its cleavage products play on saposin production, sphingolipid levels and lipid homeostasis; 3) Interrogate the effects of Pgrn haploinsuffi- ciency on lysosomal protease and lipidase pathways in humanized models. Upon successful completion of the proposed research, we will have gained understanding of how PGRN impacts downstream lysosomal processes such as protease and sphingolipidase activity, TDP-43 and sphingolipid breakdown, and overall protein and lipid homeostasis. This contribution is significant because it will lead to a comprehensive understanding of the complex, age- and disease-associated events associated with Pgrn haploinsufficiency. This will further translate into better, more rationally targeted approaches to therapy in FTLD-Pgrn and allow better understanding of the basic biology of the lysosome, how proteases and sphingolipidases can be coordinately regulated and how dysfunctional protein and lipid metabolism contribute to FTLD pathogenesis.

项目摘要 程序努尔蛋白基因的功能丧失突变（PGRN单倍不足）引起遗传形式的 FTLD带有TDP-43包含物。 PGRN蛋白及其生物活性裂解片段，“颗粒蛋白”， PGRN运输于溶酶体 作为伴奏蛋白（PSAP）的异二聚体。 PSAP调节鞘脂的水平，这是一个重要的 脂质类别在细胞内信号传导，膜运输和凋亡中作用。具体 PGRN单倍症对蛋白酶生物学，鞘脂代谢以及PGRN和PGRN和PGRN的影响 PSAP协同调节蛋白质，脂质稳态在很大程度上取得了不良状态。我们的目标是填补 通过描述PGRN及其的复杂，下游效应及其的这些主要差距 裂解产物溶酶体功能。我们的长期目标是了解衰老和疾病如何 相关的溶酶体功能障碍促进神经退行性疾病。在此应用程序中，我们的整体 目的是确定PGRN单倍不足如何影响下游过程，例如蛋白酶 和鞘脂酶活性，TDP-43和鞘脂分解，总体蛋白质和脂质 稳态。我们的中心假设是，PGRN单倍度不足，通过调节CTSD活性， 赋予蛋白质和脂质代谢的“双重命中”，这损害了TDP-43和Sphingolipid 降解，最终导致对溶酶体功能的负面影响和 细胞健康。我们工作的理由是，通过了解PGRN，PSAP及其如何 切割产物调节蛋白质和脂质代谢，我们将获得对机制的关键见解 神经退行性疾病病理生理学。这是我们提出以下特定目标：1） 确定PGRN及其切割产品如何影响CTSD介导的TDP-43崩溃和 蛋白质稳态； 2）了解PGRN及其切割产品对saposin的影响 生产，鞘脂水平和脂质稳态； 3）询问PGRN单倍苏联的影响 人性化模型中溶酶体蛋白酶和脂肪酶途径的效率。成功 拟议研究的完成，我们将了解PGRN的影响 下游溶酶体过程，例如蛋白酶和鞘脂酶活性，TDP-43和 鞘脂分解，总体蛋白质和脂质稳态。这项贡献很重要 因为这将导致对复杂，年龄和疾病相关的全面理解 与PGRN单倍体不足相关的事件。这将进一步转化为更好，更合理地 有针对性的FTLD-PGRN治疗方法，并可以更好地了解 溶酶体，蛋白酶和鞘脂酶如何协调调节以及功能失调 蛋白质和脂质代谢有助于FTLD发病机理。