Modulation of Cellular Clearance to Treat Human Disease

这个项目的目标是获得更深入的了解机制，调节溶酶体在一个 努力寻找新的工具来调节其功能。这些知识可能会直接影响 开发溶酶体贮积病（LSD）的治疗方案，这是一组超过50种遗传性疾病， 具有进行性和多系统表型的疾病，主要影响儿童。2009年我们 发现溶酶体功能和自噬受全局转录调控， 由主基因TFEB介导（Sardiello等Science 2009; Settembre等Science，2011）。这 调节途径允许溶酶体响应环境线索，如饥饿，物理 运动、感染和各种压力条件。TFEB介导溶酶体至细胞核信号传导 该机制起源于溶酶体表面并由mTORC 1激酶调节。感应 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，Dev Cell，2011，Decressac等，PNAS，2013）。尽管 在这些令人兴奋的发展中，我们对TFEB是如何被 调节在转录和翻译后水平，以及我们如何可以调节溶酶体 功能和细胞清除来治疗人类疾病。该项目旨在通过以下方式消除这些差距：1） 剖析负责TFEB转录调控的分子和发育线索， 稳态条件下TFEB表观遗传景观的定义; 2）确定介导 TFEB核出口和参与者。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）; 3）研究 调节溶酶体功能的TFEB替代途径，以确定新的信号传导途径 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.