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 颗粒蛋白前体基因的功能缺失突变（Pgrn单倍不足）导致遗传形式的 含TDP-43夹杂物的FTLD。PGRN蛋白及其生物活性切割片段，“颗粒蛋白”， 直接调节溶酶体蛋白酶组织蛋白酶D（CTSD）的活性。PGRN运输至溶酶体 作为与鞘脂激活蛋白原（PSAP）的异二聚体。PSAP调节鞘脂的水平，这是一个重要的 一类在细胞内信号传导、膜运输和细胞凋亡中起作用的脂质。具体 Pgrn单倍不足对蛋白酶生物学、鞘脂代谢的影响以及PGRN和 PSAP协调调节蛋白质和脂质稳态仍然在很大程度上没有解决。我们的目标是填补 这些知识的主要差距，通过描绘复杂的，下游的影响PGRN及其 裂解产物对溶酶体功能的影响。我们的长期目标是了解衰老和疾病- 相关的溶酶体功能障碍促进神经变性疾病。在这个应用程序中，我们的整体 目的是确定Pgrn单倍不足如何影响下游过程，如蛋白酶 和鞘脂酶活性，TDP-43和鞘脂分解，以及总蛋白质和脂质 体内平衡我们的中心假设是Pgrn单倍不足，通过调节CTSD活性， 对蛋白质和脂质代谢产生“双重打击”，从而损害TDP-43和鞘脂 降解，最终导致对溶酶体功能的负面下游后果， 细胞健康我们工作的基本原理是，通过了解PGRN，PSAP及其 裂解产物调节蛋白质和脂质代谢，我们将获得关键的洞察机制 神经退行性疾病的病理生理学。因此，我们提出以下具体目标：1） 确定PGRN及其裂解产物如何影响CTSD介导的TDP-43分解， 蛋白质稳态; 2）了解PGRN及其裂解产物对saposin的影响 生产，鞘脂水平和脂质体内平衡; 3）询问Pgrn单倍素的影响， 在人源化模型中对溶酶体蛋白酶和脂酶途径的作用。一旦成功 完成拟议的研究，我们将了解PGRN如何影响 下游溶酶体过程如蛋白酶和鞘脂酶活性，TDP-43和 鞘脂分解以及整体蛋白质和脂质体内平衡。这一贡献意义重大 因为它将导致对复杂的，与年龄和疾病相关的 与Pgrn单倍不足相关的事件。这将进一步转化为更好的，更合理的 有针对性的方法来治疗FTLD-Pgrn，并允许更好地理解的基础生物学的 溶酶体，蛋白酶和鞘脂酶如何协调调节以及功能障碍如何 蛋白质和脂质代谢有助于FTLD发病机制。