Integrated Multi-scale Adhesive Dynamics Modeling of T-lymphocyte Homing Daniel A. Hammer (PI), Gary T. Koretzky (co-PI) Project Summary The proper functioning of the immune system relies on the ability of immune cells such as T-lymphocytes to travel throughout the body and home to specialized tissues to transfer molecular information. Intimate molecular communication between cells is crucial to immune cells'maturation and activation. It has been established that lymphocyte trafficking from the blood stream and the lymphatic tissues is controlled by molecular """"""""zip-codes"""""""" that identify the precise location where lymphocytes need to travel. The zip-code is the combination of adhesion molecules and chemokines/chemokine receptor pairs on the lymphocyte and host tissue, such that when there is a """"""""match"""""""", the lymphocyte can respond by adhering rapidly. The goal of this proposal is to develop novel computational tools to understand how lymphocytes integrate and convert molecular signals into the activation of leukocyte integrins to mediate specific adhesion under flow. The basis of these tools is the integration of signal transduction networks, either involving chemokine activation of G-proteins or the assembly of a """"""""signalsome', into Adhesive Dynamics, a simulator of cell adhesion. This integrated method can readily predict the rate of lymphocyte firm adhesion. The main questions of investigation are, how are multiple chemokine signals integrated within a single network, how does the signalsome assemble and reinforce integrin and adhesion strength, and how does the time-scale for lymphocyte adhesion depend on molecular density and identity of lymphocyte surface receptors? We will make predictions on the rate of lymphocyte stopping, and compare to measurements of adhesion for Jurkat cells and primary T-cells from mice. We will make use of molecular engineering to knock down or express signaling components within these cell lines, and perform corresponding simulations to verify the accuracy of our methods. The net result will be a novel computational tool with the ability to predict the location of lymphocyte adhesion.

Public Health Relevance

Integrated Multi-scale Adhesive Dynamics Modeling of T-lymphocyte Homing Daniel A. Hammer (PI), Gary T. Koretzky (co-PI) Relevance To carry out their immunological function, lymphocytes must travel to specific locations within the body. The homing of lymphocyte sublines is controlled through a complex molecular zip- coding, in which surface receptors on lymphocytes bind ligands on blood vessel walls, and the combination of molecular codes leads to the fidelity of homing. It is not understood how lymphocytes integrate molecular information through internal signal transduction networks to make decisions on where to adhere. The goal of this proposal is to develop a computational framework for modeling the interplay between adhesion and lymphocyte signal transduction to gain a better understanding of the factors that control lymphocyte homing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI082292-02
Application #
7895491
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2009-07-17
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$385,555
Indirect Cost
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Sklarz, Tammarah; Guan, Peng; Gohil, Mercy et al. (2017) mTORC2 regulates multiple aspects of NKT-cell development and function. Eur J Immunol 47:516-526
MacKay, Joanna L; Hammer, Daniel A (2016) Stiff substrates enhance monocytic cell capture through E-selectin but not P-selectin. Integr Biol (Camb) 8:62-72
Dominguez, George A; Anderson, Nicholas R; Hammer, Daniel A (2015) The direction of migration of T-lymphocytes under flow depends upon which adhesion receptors are engaged. Integr Biol (Camb) 7:345-55
Vargo, Kevin B; Zaki, Ajlan Al; Warden-Rothman, Robert et al. (2015) Superparamagnetic iron oxide nanoparticle micelles stabilized by recombinant oleosin for targeted magnetic resonance imaging. Small 11:1409-13
Paszek, Matthew J; DuFort, Christopher C; Rossier, Olivier et al. (2014) The cancer glycocalyx mechanically primes integrin-mediated growth and survival. Nature 511:319-25
Dominguez, George A; Hammer, Daniel A (2014) Effect of adhesion and chemokine presentation on T-lymphocyte haptokinesis. Integr Biol (Camb) 6:862-73
Hammer, Daniel A (2014) Adhesive dynamics. J Biomech Eng 136:021006
Joshi, Rohan P; Schmidt, Amanda M; Das, Jayajit et al. (2013) The ? isoform of diacylglycerol kinase plays a predominant role in regulatory T cell development and TCR-mediated ras signaling. Sci Signal 6:ra102
Beste, Michael T; Lee, Dooyoung; King, Michael R et al. (2012) An integrated stochastic model of ""inside-out"" integrin activation and selective T-lymphocyte recruitment. Langmuir 28:2225-37
Lee, Dooyoung; Kim, Jiyeon; Beste, Michael T et al. (2012) Diacylglycerol kinase zeta negatively regulates CXCR4-stimulated T lymphocyte firm arrest to ICAM-1 under shear flow. Integr Biol (Camb) 4:606-14

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