Role of LIPL-4 in lysosomal lipolysis and aging

LIPL-4 在溶酶体脂肪分解和衰老中的作用

• 批准号: 9217535
• 负责人: Louis Rene Lapierre
• 金额: $ 23.7万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217535
• 关键词: Acid Lipase; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animals; Autophagocytosis; Autophagosome; Biological Assay; Caenorhabditis elegans; Cell Culture Techniques; Cells; Chemicals; Cholesterol; Cholesterol Esters; Coupled; Data; Development; Disease; Disease model; Enzymes; Functional disorder; Genes; Genetic Screening; Grant; Homeostasis; Human; Hydrolysis; Impairment; Insulin; Lead; Learning; Link; Lipase; Lipids; Lipolysis; Longevity; Lysosomes; Mammalian Cell; Mediating; Metabolism; Methods; Microscopy; Modeling; Molecular; Mus; Nematoda; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nutrient; Organelles; Organism; Paralysed; Pathologic; Pathway interactions; Pharmacology; Phase; Physiological; Process; Proteins; Proteomics; Publishing; Recycling; Reporter; Reporting; Research; Research Proposals; Risk; Role; Scientist; Senile Plaques; Signal Pathway; Signal Transduction; Sirolimus; Site; System; Testing; Therapeutic; Translating; Vesicle; Work; Yeasts; abeta toxicity; age related; aging population; base; cholesterol trafficking; experimental study; fly; high throughput screening; innovation; insulin signaling; lipid metabolism; new technology; novel; novel therapeutics; overexpression; prevent; proteostasis; sensor; skills; sterol esterase; therapeutic target; transcription factor

PROJECT SUMMARY Dysfunctions in the autophagy/lysosomal pathway are pathologically significant in the development of age-related diseases, such as neurodegeneration. In C. elegans, several longevity models rely on increased autophagy for lifespan extension, suggesting a critical role for autophagy in aging. Animals can also enjoy longer lifespan when the nutrient-sensor TOR, a negative regulator of autophagy, is inhibited. Nonetheless, how autophagy mediates its beneficial effects is poorly understood. We recently reported that autophagy could be induced by over-expressing the putative lysosomal lipase LIPL-4, which resulted in a significant lifespan extension, enhanced lipolysis and altered TOR signaling, suggesting a link between lipid metabolism, autophagy and aging. LIPL-4 displays strong homology with human lysosomal acid lipase (LAL), a key enzyme in the hydrolysis of cholesterol via autophagy. Notably, impaired LAL-mediated cholesterol processing has been linked to the development of Alzheimer's disease. My new results show that over-expressing LIPL-4 ameliorates Aβ toxicity in a C. elegans model of Alzheimer's disease. Therefore, this proposal will test the hypothesis that LIPL-4, similar to LAL, mediates lysosomal lipid hydrolysis and will aim to elucidate how LIPL-4 modulates autophagy and mitigates Aβ toxicity. In Aim 1, I will confirm the intracellular site of action of LIPL-4 and determine its relationship to TOR signaling. In Aim 2, I will test whether LIPL-4 and LAL are functionally interchangeable in C. elegans. The mechanism of action by which LIPL-4 induces autophagy and modulates aging will also be elucidated. In Aim 3, I will investigate how LIPL-4 mediates a delay in the onset of Alzheimer's disease in C. elegans. I will also perform a high-throughput screen (HTS) to discover novel and specific candidate that activates LAL-mediated lipolysis, as a strategy against neurodegeneration. By determining the role of lysosomal lipolysis in aging, my proposal will provide a basis on which novel drugs can be discovered to prevent Alzheimer's disease. The 2-year postdoctoral K99 phase will consist in the characterization of the role of LIPL-4 in lysosomal function, lipid metabolism and aging. Cell-based assay reporter systems compatible with HTS will be used to find novel drugs to enhance LAL expression. The 3-year independent R00 phase will serve to further understand the role of LIPL-4 in lysosomal lipolysis, lipid signaling and aging and expand into studies on lipid dynamics, metabolism and proteostasis. Lead candidate activators of LAL will be validated using Alzheimer's disease model in C. elegans and cell culture models. This proposal includes cutting-edge approaches, such as proteomic analyses, CARS microscopy and HTS combined with the innovative use of disease models in C. elegans. In summary, the K99/R00 grant represents a unique opportunity for me to learn new technologies and develop my professional skills to successfully transition into an independent scientist in aging research.

项目总结

项目成果

Visible light reduces C. elegans longevity.

• DOI: 10.1038/s41467-018-02934-5
• 发表时间: 2018-03-02
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: De Magalhaes Filho CD;Henriquez B;Seah NE;Evans RM;Lapierre LR;Dillin A
• 通讯作者: Dillin A

Emerging topics in C. elegans aging research: Transcriptional regulation, stress response and epigenetics.

• DOI: 10.1016/j.mad.2018.08.001
• 发表时间: 2019-01
• 期刊: Mechanisms of ageing and development
• 影响因子: 5.3
• 作者: Denzel MS;Lapierre LR;Mack HID
• 通讯作者: Mack HID

Reduced ech-6 expression attenuates fat-induced lifespan shortening in C. elegans.

• DOI: 10.1038/s41598-022-07397-9
• 发表时间: 2022-03-01
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Liu YJ;Gao AW;Smith RL;Janssens GE;Panneman DM;Jongejan A;van Weeghel M;Vaz FM;Silvestrini MJ;Lapierre LR;MacInnes AW;Houtkooper RH
• 通讯作者: Houtkooper RH

Give me a SINE: how Selective Inhibitors of Nuclear Export modulate autophagy and aging.

• DOI: 10.1080/23723556.2018.1502511
• 发表时间: 2018
• 期刊: Molecular & cellular oncology
• 影响因子: 2.1
• 作者: Kumar AV;Thakurta TG;Silvestrini MJ;Johnson JR;Reenan RA;Lapierre LR
• 通讯作者: Lapierre LR