Mapping and Therapeutic Hijacking of Lysosomal Transport
溶酶体运输的绘图和治疗劫持
基本信息
- 批准号:10686547
- 负责人:
- 金额:$ 138.52万
- 依托单位:
- 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:2023-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AtlasesAutophagocytosisCell Surface ProteinsCell membraneCell physiologyCell surfaceCellsChimera organismCommunicationCuesDevelopmentDiseaseDrug Delivery SystemsDrug TargetingEndocytosisEquilibriumExtracellular ProteinExtracellular SpaceImmunotherapyIn VitroKineticsLigandsLysosomesMalignant NeoplasmsMammalian CellMapsMethodsModalityModelingMusNeurodegenerative DisordersOrganOrganellesOutcomePathway interactionsPinocytosisProcessProliferatingProtein EngineeringProtein SecretionProteinsProteomeRecyclingRoleSignal TransductionSurfaceTherapeuticTimeTissuesTranslatingTransmembrane TransportWorkcancer cellcell typechemoproteomicsdesigndetection of nutrientextracellularimmune checkpointin vivoinnovationmacromoleculenovelnovel strategiesnovel therapeuticsprotein degradationprotein functionprotein transportreceptorresponsetraffickingtranslational applicationstransmission processtumor
项目摘要
PROJECT SUMMARY/ABSTRACT
The mammalian cell surface proteome (surfaceome) is a hub of communication that transmits information
from the extracellular space to the intracellular machinery, controlling proliferation and cell fate. A major
regulatory endpoint of the surfaceome and extracellular proteome is the lysosome. As the primary organelle for
breaking down various macromolecules, lysosomes are central to nutrient sensing, storage and distribution, as
well as modulating cell surface protein abundance. The transport of membrane and secreted proteins from the
extracellular space to lysosomes occurs through many discrete processes, including autophagy, endocytosis,
and pinocytosis. Given the critical roles of the surfaceome and lysosomes in integrating signals from the
extracellular space, the trafficking between these two compartments is highly regulated across different cell types
and in response to specific cues. Dysregulation of this trafficking is a hallmark of cancer and neurodegenerative
diseases that disrupts the homeostatic balance between cell surface protein function, recycling, and lysosomal
degradation. While an understanding of all proteins which move between the extracellular space and lysosomes
remains incomplete, this pathway has proven transformative for targeted drug delivery and new therapeutic
modalities like targeted protein degradation.
An atlas of all potential proteins which can be used as lysosome targeting moieties in specific contexts
would substantially expand therapeutic options for numerous diseases. However, a lack of methods for studying
surface-to-lysosome trafficking in organ and cell-type specific ways has limited our ability to rationally hijack this
pathway for translational applications. What is needed is a functional map across tissues, time, and disease
states for identifying potential receptors that could be used to drive targeted protein degradation, as well as more
broadly enable widespread utilization of selective trafficking pathways. In this proposal, I describe an innovative
approach which unites whole lysosome isolation from distinct mouse tissues with chemoproteomics to identify
proteins that traffic to lysosomes from the plasma membrane and extracellular space. We propose to map across
tissues and time the transport of extracellular proteins to lysosomes both in healthy tissues and in murine tumor
models. By correlating these in vivo discovery efforts with a novel high-throughput method for in vitro analysis of
lysosome translocation kinetics, we will facilitate the rational utilization of new trafficking proteins. We go on to
propose conceptual advances in designing ligands to harness lysosomal transport for targeted degradation of
disease-causing extracellular proteins using de novo protein design. Finally, we propose a new approach to
immunotherapy that directly translates our in vivo, in vitro, and ligand development efforts via lysosome targeting
chimeras (LYTACs) that selectively degrade immune checkpoint proteins from cancer cells. The outcomes of
this proposal will help revolutionize therapeutic design and drug delivery by mapping the scope and function of
extracellular-to-lysosome communication.
项目总结/摘要
哺乳动物细胞表面蛋白质组(surfaceome)是传递信息的通讯枢纽
从细胞外空间到细胞内机器,控制增殖和细胞命运。一个主要
表面蛋白质组和细胞外蛋白质组的调节终点是溶酶体。作为主要的细胞器,
溶酶体分解各种大分子,是营养感测、储存和分布的中心,
以及调节细胞表面蛋白质丰度。细胞膜和分泌蛋白的转运
细胞外空间到溶酶体的转化通过许多离散过程发生,包括自噬,内吞作用,
和胞饮作用。鉴于表面体和溶酶体在整合来自细胞的信号中的关键作用,
细胞外空间,这两个区室之间的运输在不同的细胞类型中受到高度调节
and in response响应to specific具体cues线索.这种运输的失调是癌症和神经退行性疾病的标志。
破坏细胞表面蛋白质功能、回收和溶酶体之间稳态平衡的疾病
降解虽然对所有在细胞外空间和溶酶体之间移动的蛋白质的理解
尽管该途径仍然不完整,但已证明其对于靶向药物递送和新的治疗方法具有变革性意义。
例如靶向蛋白质降解。
可在特定情况下用作溶酶体靶向部分的所有潜在蛋白质的图谱
将大大扩展许多疾病的治疗选择。然而,缺乏研究方法,
器官和细胞类型特异性的表面到溶酶体的运输限制了我们合理地劫持这一点的能力。
翻译应用的途径。我们需要的是一个跨组织、跨时间、跨疾病的功能图谱
用于识别可用于驱动靶蛋白降解的潜在受体的状态,以及更多
使有选择的贩运途径得到广泛利用。在这篇文章中,我描述了一个创新的
将从不同小鼠组织中分离的整个溶酶体与化学蛋白质组学相结合的方法,
从质膜和细胞外空间运输到溶酶体的蛋白质。我们建议在地图上
在健康组织和小鼠肿瘤中,细胞外蛋白质转运到溶酶体的组织和时间
模型通过将这些体内发现努力与用于体外分析的新的高通量方法相关联,
溶酶体易位动力学,我们将促进新的运输蛋白的合理利用。我们爬到
提出了设计配体的概念性进展,以利用溶酶体转运靶向降解
使用从头蛋白质设计的致病细胞外蛋白质。最后,我们提出了一种新的方法,
免疫治疗,直接转化我们在体内,体外,和配体开发的努力,通过溶酶体靶向
嵌合体(LYTAC),其选择性地降解来自癌细胞的免疫检查点蛋白。的成果
该提案将有助于通过绘制治疗设计和药物输送的范围和功能,
细胞外到溶酶体的通讯。
项目成果
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