2016 — 2019 |
Rangamani, Padmini |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Collaborative Research: Isothermal Phase Transition in Lipid Vesicles and Swell-Burst Cycles @ University of California-San Diego
In this project the PI, using a combination of theory, simulations and experiments, will investigate the complexities of lipid membranes. The project combines concepts from the fields of polymer physics, membrane mechanics and bioengineering, surface and interface science, and soft condensed matter to study the organization of biological membranes. The modeling efforts will develop new and novel mathematics and new numerical schemes to solve the resulting differential equations. The current understanding of how multi-component giant unilamellar vesicles (GUVs) respond to osmotic pressure differentials is incomplete, and experimental observations indicate that a non-linear model coupling membrane dynamics with 3D fluid flow is needed to fully explain the non-linearities of the system. Developing this theoretical framework and providing insight into the underlying physics is crucial for the understanding of how membranes undergo morphological transitions. These models will explain existing experiments and also predict membrane response to different osmotic loads and membrane compositions. Understanding this process is important for better experimental design of in vitro reconstituted systems such as vesicles and also cellular systems. The work is inherently interdisciplinary, using mathematics and physics in biological systems. Both fields will benefit from this approach to studying biological phenomena; the theory will be grounded in experiments and also make predictions to design future experiments. This research will be integrated into the teaching efforts of the PIs in developing new courses at the interface of engineering and biology. The PIs will continue their efforts in enhancing diversity in the UC system while pursuing the research program.
Biological membranes are inherently heterogeneous mixtures of lipids and proteins. A key characteristic of this heterogeneity is the coexistence of liquid-ordered and liquid-disordered phases. This coexistence is thought to be the key organizing principle for the formation of lipid rafts. Studying the formation and organization of the different phases in cellular system is experimentally challenging, given the complex nature of the cells. Giant unilamellar vesicles with controlled compositions, allow us to study lipid behavior in bilayer membranes and gain insight into phase behavior which is important for understanding cellular membranes. Although GUVs are used widely experimentally, our theoretical understanding of lipid phase separation remains rudimentary, since existing models focus on the line tension between preexisting domains and not on domain growth and swell-burst cycles, which are the features observed experimentally. The objectives of this project are to formulate quantitative models of isothermal phase separation and swell-burst cycle in multi-component GUVs and test model predictions experimentally. STUDY 1-DYNAMICS OF SOLUTE EFFLUX. We will use theory, simulations, and experiments to understand the factors that control pore radius, vesicle radius, and the lifetime of the pore. STUDY 2-PHASE SEPARATION IN OSMOTICALLY STRESSED VESICLES. Using a viscoelastic model of multi-component lipid membranes, we will investigate the role of governing energetics in domain growth versus true phase transitions. We will experimentally test the model predictions by tuning the osmotic pressure difference, lipid composition, and sample temperature. STUDY 3-COUPLING BETWEEN DOMAIN FORMATION AND SWELL-BURST CYCLES. In this study, we will develop the mathematical framework to model the complete dynamics of the oscillatory phase separation coupled with the swell-burst cycle observed in the preliminary experiments. This model will combine the dynamics of pore formation outlined in Study 1, with the domain growth model including membrane viscosity in Study 2. The significance of the proposed activities lies in its promise to not only elucidate the fundamental properties of mixtures of lipids reduced dimensional, bilayer configuration but also furnish design principles for designing synthetic protocellular compartments for applications spanning in vitro production of proteins, chemistry in confinement, and delivery of biomedically relevant cargo (e.g., enzymes, drugs, and imaging agents). Using a combination of theory, simulations and experiments, this work will be able to provide insight into the complexities of lipid membranes. The long-term impact of the proposed activities stems from the fact that the project combines concepts from the fields of polymer physics, membrane mechanics and bioengineering, surface and interface science, and soft condensed matter. The modeling efforts outlined here will result in new and novel mathematics and new numerical schemes to solve the resulting differential equations.
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0.916 |
2016 |
Del Alamo, Juan Carlos (co-PI) [⬀] Rangamani, Padmini |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Mechbio Symposium: Finding the Pieces, Building the Puzzle; University of California-San Diego; La Jolla, California; August 4-5, 2016 @ University of California-San Diego
The "Mechbio Symposium: Finding the Pieces, Building the Puzzle; University of California, San Diego; August 4-5, 2016" will be a forum where theorists, computational scientists, and experimentalists from both the STEM disciplines and the Life Sciences can begin a conversation about integrating different disciplines and methodologies to advance the field of quantitative multiscale mechanobiology. In order to have a cross-sectional representation of these fields, at least 40-50 participants will attend. This number will allow the different disciplines to be well-represented, without being overwhelmingly large. There are many annual societies with meetings on broad themes, but this meeting will focus on the theme of mechanics in biology across the different scales from cells to tissues to organs. In addition to platform talks and poster sessions, the meeting will also foster collaborative efforts and potential partnerships between mentors and mentees. Break out sessions throughout the meeting with small groups will be given the task of laying out a list of specific aims to answer the question "How would you put together a cell's/tissue/organ mechanome"? By engaging an audience across different career levels, and by disseminating the conference program to a larger audience as a journal report, this symposium will enable us to highlight the importance of mechanics at the organ, tissue, and cellular level. The organizers will actively recruit speakers and participants at different career stages, gender, and underrepresented minorities.
The focus of the Symposium on mechanobiology and fostering collaboration among the multiple disciplines is of direct interest to the goals of the Biomechanics and Mechanobiology program.
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0.916 |
2019 — 2022 |
Holst, Michael (co-PI) [⬀] Llewellyn Smith, Stefan (co-PI) [⬀] Rangamani, Padmini |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Collaborative Research: Modulus: Modeling and Experimental Investigation of Protein Crowding On Lipid Bilayers @ University of California-San Diego
Cellular membranes separate the contents of the cell from the environment. In addition to demarcating cellular boundaries, these membranes perform critical functions such as the uptake of nutrients and drugs into the cell and ejection of material out of the cell. Membranes perform these functions by interacting with many different proteins. Therefore, understanding how membrane-protein interactions take place is critical for gaining insight not just into how cells function but also for understanding how viruses can hijack cells or how better drug delivery systems can be designed. The work proposed here will result in new computational algorithms and experimental tools to understand how cellular membranes interact with proteins to regulate these fundamental functions. The insights generated from our effort will fill major gaps in current understanding about how the cell membrane can change its shape to affect its function. These insights have the potential to benefit society in multiple ways including (i) improving understanding of the mechanisms that pathogens use to invade cells, suggesting new therapeutic strategies; (ii) inspiring the design of better systems for drug and gene delivery, and; (iii) revealing fundamental mechanisms that structure and organize soft matter, potentially leading to improvements in technologies that rely on such materials including surfactants, cosmetics, fuels, and foods.
Membrane curvature plays a role in nearly every cellular function, in both health and disease. The curvature of the membrane is mediated by many proteins that interact with lipids. In this proposal, we will develop new theoretical and computational models of membrane-protein interactions with a focus on understanding how protein crowding can lead to membrane curvature generation. This effort combines multiscale modeling of membrane bending with quantitative detailed experimental measurements of membrane surface coverage, steric pressure, and curvature. The multiscale modeling efforts include coarse-grained models of lipid bilayer-protein interactions that will inform the continuum models of membrane curvature generation. The team of investigators includes an experimental biophysicist, a theoretical biophysicist, and mathematicians. The insights generated from our efforts will fill major gaps in current understanding of how membrane curvature is generated and stabilized. We also anticipate these applications driving additional development of the theory and numerical treatment of nonlinear geometric partial differential equations posed on surfaces with constraints. Additionally, the team of investigators will participate in outreach and educational activities, including programs for high school students, undergraduate research opportunities, and new course development. This award was co-funded by Systems and Synthetic Biology in the Division of Molecular and Cellular Biosciences and the Mathematical Biology Program of the Division of Mathematical Sciences.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
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0.916 |
2020 — 2021 |
Rangamani, Padmini |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Modeling and Analysis of the Mechanochemical Processes That Govern Clathrin-Mediated Endocytosis @ University of California, San Diego
Project Summary Endocytosis is the process of uptake of cargo and ?uid 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. Speci?cally, the work of the principal investigator, supported by ?ndings from others has identi?ed that membrane tension governs CME through a snapthrough instability. Building on these preliminary ?ndings, 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 ?laments 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.
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0.916 |