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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要颗粒体蛋白前体基因的功能丧失突变（Pgrn 单倍体不足）导致遗传形式含有 TDP-43 内含物的 FTLD PGRN 蛋白及其生物活性裂解片段“颗粒蛋白”。直接调节溶酶体蛋白酶组织蛋白酶 D (CTSD) 的活性。作为与前塞塞辛 (PSAP) 的异二聚体，可调节鞘脂的水平，鞘脂是一种重要的物质。在细胞内信号传导、膜运输和细胞凋亡中发挥作用的一类脂质。 Pgrn 单倍体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在很大程度上仍未得到解决。通过描述 PGRN 及其下游的复杂影响来描述这些主要的知识差距我们的长期目标是了解衰老和疾病是如何影响的。相关的溶酶体功能障碍会促进神经退行性疾病。目标是确定 Pgrn 单倍体不足如何影响下游过程，例如蛋白酶和鞘脂酶活性、TDP-43 和鞘脂分解以及总体蛋白质和脂质我们的中心假设是 Pgrn 单倍体不足，通过 CTSD 活性的调节，对蛋白质和脂质代谢造成“双重打击”，从而损害 TDP-43 和鞘脂降解，最终导致下游对溶酶体功能的负面影响我们工作的基本原理是了解 PGRN、PSAP 及其如何发挥作用。裂解产物调节蛋白质和脂质代谢，我们将获得对其机制的重要见解因此，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 分解和蛋白质稳态；2) 了解 PGRN 及其裂解产物对皂苷的影响生产、鞘脂水平和脂质稳态；3) 探究 Pgrn haploinsuffi- 的影响成功研究人源化模型中溶酶体蛋白酶和脂质酶途径的效率。完成拟议的研究后，我们将了解 PGRN 如何影响下游溶酶体过程，例如蛋白酶和鞘脂酶活性、TDP-43 和鞘脂分解以及整体蛋白质和脂质稳态的贡献是显着的。因为它将导致对与年龄和疾病相关的复杂问题的全面理解与 Pgrn 单倍体不足相关的事件将进一步转化为更好、更合理的结果。 FTLD-Pgrn 的靶向治疗方法，可以更好地了解 FTLD-Pgrn 的基础生物学溶酶体，蛋白酶和鞘脂酶如何协调调节以及功能失调如何蛋白质和脂质代谢有助于 FTLD 发病机制。