Modulation of Cellular Clearance to Treat Human Disease

这个项目的目标是对调节溶酶体的机制有更深入的了解。 努力寻找新的工具来规范其功能。这一知识可能会对 溶酶体贮积性疾病(LSD)治疗方案的发展，LSD是一组超过50人的遗传性疾病 具有进行性和多系统表型的疾病，主要影响儿童。在2009年，我们 发现溶酶体功能和自噬受到全球转录调控的影响，这是 由主要基因TFEB介导(Sardiello等人)。《科学》2009；Settembre等人。科学，2011)。这 调节途径允许溶酶体对环境提示做出反应，如饥饿、物理 运动、感染和各种压力条件。TFEB介导溶酶体核信号转导 一种起源于溶酶体表面并受mTORC1K调节的机制。归纳 通过TFEB的溶酶体生物发生和自噬已被证明是促进细胞清除的有效工具 LSD和神经退行性疾病(Medina等人，Dev Cell，2011年，Decressac等人，PNAS，2013年)。尽管 在这些令人兴奋的发展中，我们对TFEB是如何理解的仍有几个知识空白 转录和翻译后水平的调控以及我们如何调控溶酶体 治疗人类疾病的功能和细胞清除。该项目旨在通过以下方式解决这些差距：1) 剖析与TFEB转录调控有关的分子和发育信号 稳态条件下TFEB表观遗传景观的定义；2)确定中介途径 TFEB核出口和涉及的参与者。对这些途径的深入了解可能会导致 确定抑制或加强TFEB核出口的工具(和潜在目标)和3)研究 TFEB以外的调节溶酶体功能的通路，以努力识别新的信号通路 以及直接或间接调节溶酶体功能的分子。这些研究的结果将是 有助于确定安全有效地调节溶酶体清除的新策略和工具 储存在各种疾病中。

The goal of this project is to gain a deeper knowledge on the mechanisms that regulate the lysosome in an effort to identify novel tools to regulate its function. This knowledge could have a direct impact on the development of therapeutic options for lysosomal storage diseases (LSDs), a group of over 50 inherited diseases with a progressive and multisystemic phenotype, which mostly affect children. In 2009 we discovered that lysosomal function and autophagy are subject to a global transcriptional regulation, which is mediated by the master gene TFEB (Sardiello et al. Science 2009; Settembre et al. Science, 2011). This regulatory pathway allows the lysosome to respond to environmental cues such as starvation, physical exercise, infection, and a variety of stress conditions. TFEB mediates a lysosome-to-nucleus signaling mechanism that originates from the lysosomal surface and is regulated by the mTORC1 kinase. Induction lysosomal biogenesis and autophagy via TFEB has proven to be a potent tool to promote cellular clearance in LSDs and neurodegenerative diseases (Medina et al, Dev Cell,2011, Decressac et al, PNAS, 2013). In spite of these exciting developments several knowledge gaps remain in our understanding of how TFEB is regulated at both transcriptional and post-translational levels and on how we could be modulate lysosomal function and cellular clearance to treat human diseases. This project aims at tackling these gaps by: 1) dissecting the molecular and developmental cues responsible for TFEB transcriptional regulation and on the definition of TFEB epigenetic landscape in steady-state conditions; 2) identifying the pathways that mediate TFEB nuclear export and the players involved. A deeper understanding of these pathways may lead to the identification of tools (and potential targets) to either inhibit or enhance TFEB nuclear export and 3) studying pathways alternative to TFEB that regulate lysosomal function in an effort to identify novel signalling pathways and molecules that regulate, either directly or indirectly, lysosomal function. The results of these studies will be instrumental in identifying new strategies and tools to safely and effectively modulate clearance of lysosomal storage in a variety of diseases.