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Modeling and analysis of the mechanochemical processes that govern clathrin-mediated endocytosis

控制网格蛋白介导的内吞作用的机械化学过程的建模和分析

基本信息

批准号：
9886057
负责人：
Padmini Rangamani
金额：
$ 30.85万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886057
关键词：
Actins Address Affect Affinity Binding Binding Proteins Biochemical Biophysics Cell membrane Cells Clathrin Communities Computer Models Coupling Cytoskeleton Data Data Set Defect Development Diffusion Disease Down-Regulation Drug Delivery Systems Endocytosis Explosion Extracellular Fluid Extracellular Space Feedback Filament Generations Genes Goals Heart Heart Diseases Homeostasis Imaging technology Knowledge Lipid Bilayers Literature Malignant Neoplasms Mammalian Cell Measures Mechanics Mediating Membrane Membrane Lipids Membrane Proteins Methods Microfilaments Mission Modeling Modification Molecular Morphology NanoPillar Nerve Degeneration Pathology Pattern Play Principal Investigator Probability Process Property Proteins Public Health Radial Receptor Signaling Regulation Research Role Scheme Shapes Site Structure Surface Testing Theoretical model United States National Institutes of Health Vesicle Work Yeasts computerized tools density design experimental study human disease in vivo in vivo evaluation insight mathematical methods membrane model model development nanomedicine open source polymerization predictive modeling repository simulation spatiotemporal uptake

项目摘要

Project Summary Endocytosis is the process of uptake of cargo and ﬂuid from the extracellular space to inside the cell; defects in endo- cytosis contribute to a wide spectrum of diseases including cancer, neurodegeneration, and heart disease. Clathrin- mediated endocytosis (CME) is an archetypal example of a membrane deformation process where multiple variables such as pre-existing membrane curvature, membrane bending due to the protein machinery, membrane tension regula- tion, and actin-mediated forces govern the progression of vesiculation. Advances in imaging technology have recently led to an explosion in morphological and biochemical data sets that track the progression of CME. While computa- tional modeling of lipid bilayers has provided insight into the mechanics of membranes in general, a mechanistic and predictive framework that can relate the plasma membrane composition and plasma membrane-cytoskeleton interac- tions to the progression and robustness of CME is missing, resulting in a gap between the experimental advances in the study of CME and a predictive, mechanistic framework for harnessing CME for nanomedicines. Preliminary data from our group has shown that membrane tension plays an important role in governing the progression of CME. How does membrane tension govern the progression of CME in the presence of membrane-protein interactions and membrane-cytoskeleton interactions? Substantial preliminary data in this application supports the working hypothesis that membrane tension is a dynamic quantity that evolves over the progression of CME to modulate the energy bar- rier associated with vesiculation. Speciﬁcally, the work of the principal investigator, supported by ﬁndings from others has identiﬁed that membrane tension governs CME through a snapthrough instability. Building on these preliminary ﬁndings, the goal of the proposed work is to elucidate the fundamental biophysical principles of CME. In the proposed work, we have outlined three hypotheses and aims aims that will enable us to close this knowledge gap. Aim 1 will test the hypothesis that membrane-protein interactions during CME are regulated by membrane tension dynamically; this hypothesis will be tested using new theoretical and computational models that will incorporate the energetics of mem- brane-protein interactions and in-plane diffusion of proteins along the membrane. It is expected that membrane tension will emerge as a dynamic modulator of local membrane deformations due to protein interactions. Aim 2 will test the hypothesis that force generation during CME depends on the actin organization around an endocytic pit; this hypoth- esis will focus on the development of theoretical models that incorporate the dynamic and stochastic actin-membrane interactions and predict the spatio-temporal organization of actin ﬁlaments around an endocytic pit. Aim 3 will test the hypothesis that pre-existing curvature of the membrane can modify the energy landscape of the progression of CME; models will be developed to test this hypothesis using different initial curvatures of the substrate. Collectively, the insights provided by the modeling effort conducted in these three aims will provide insight into how membrane-protein and membrane-cytoskeleton interactions affect the progression of CME.

项目总结