The proper functioning of the immune system relies on 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 vessels into tissues is controlled by molecular "zip-codes" that identify the location where lymphocytes need to adhere. The zip-codes are precise, quantitative combinations of adhesion molecules and chemokines/chemokine receptor pairs on the lymphocyte and host tissue, such that when there is a "match", the lymphocyte responds 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 networks or the assembly of the SLP-76 dependent "signalosome', into Adhesive Dynamics, a simulator of cell adhesion. This integrated method, called Integrated Signaling Adhesive Dynamics (ISAD) can readily predict the rate of lymphocyte firm adhesion under flow.
The aims of this proposed work are to 1) extend our modeling of lymphocyte signal transduction networks to both chemokine signaling and the signalosome;2) to integrate these models into ISAD simulations to simulate the progressive rolling and stopping of lymphocytes on defined molecular substrates;and 3) to compare our simulations with the adhesive behavior of engineered T- lymphocytes, including Jurkat cells and T cells from knock-out mice in which SLP-76 is deleted or altered, or in which diacylglycerol kinases (DGK) have been deleted. We show preliminary results that SLP-76 defects lead to a decrease in adhesiveness, and DGK defects lead to an increase in adhesiveness. The gain of function of DGK mutants is recapitulated by simulations, confirming the validity of our modeling. We will also measure and simulate how multiple chemokine signals are integrated within a single cell to give rise to adhesion, and how knock-downs of key signaling components both in T-cells and immortalized T-cells (Jurkat cells) lead to quantitative alterations in adhesion. Our comparison between simulation and experiment, and extensive sensitivity analysis, will allow us to identify ranges of parameter values consistent with experimental observations and to elucidate the key controlling pathways in lymphocyte adhesion and homing.

Public Health Relevance

Integrated Multi-scale Adhesive Dynamics Modeling of T-lymphocyte Homing Daniel A. Hammer (PI), Gary T. Koretzky (co-PI) Relevance Human immunity requires that lymphocytes 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 signals inside of lymphocytes control the trafficking patterns of lymphocytes. 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 and hence the proper response of the immune system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI082292-04
Application #
8635275
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2009-07-17
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$423,908
Indirect Cost
$153,011
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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