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https://hdl.handle.net/2142/72146
Description
Title
Computational Studies of Autocrine Ligand Binding
Author(s)
Forsten, Kimberly Elizabeth
Issue Date
1993
Doctoral Committee Chair(s)
Lauffenburger, Douglas A.
Department of Study
Chemical Engineering
Discipline
Chemical Engineering
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Biochemistry
Engineering, Chemical
Health Sciences, Immunology
Abstract
Autocrine ligand secretion and binding to cell surface receptors regulate cell behavior in a number of important physiological functions. At the same time, some pathological conditions such as the unmitigated growth of tumors can also act through this type of stimulation. Interpretation of experimental studies of autocrine systems is complicated by both the interdependence of system variables and the difficulty in measuring central parameters including secretion rate and receptor number. A mathematical modeling approach offers hope for improved understanding of the kinetic and transport rate processes involved in autocrine cell phenomena.
In this thesis, several characteristics of autocrine systems are examined computationally. First, experimental efforts to introduce anti-ligand and anti-receptor competing molecules to the extracellular environment, as a means of inhibiting cell response or as a tool for investigating the stimulation process, are problematic. Modeling work examining the effect of both types of competitive molecules finds that lower concentrations of anti-receptor molecules are needed to obtain the same level of inhibition as with anti-ligand molecules. Further, it is shown that diffusion-limitation can play a significant role in the outcome of molecular binding competition. A comparison of substrate-dependent and -independent cell binding inhibition was made. Also, the effect of extracellular competitor addition on intracellular complex formation is examined and compared to an extracellular secretion/binding autocrine mechanism. A final observation of this modeling work is that a compartmentalized model does not fully capture events which occur close to the cell surface. Second, a Brownian dynamics simulation procedure yields an estimate of the capture probability for a secreted ligand by its own cell surface receptor. Interestingly, calculations indicate that there is only a difference of two orders of magnitude in receptor density between a cell with almost a zero probability of capture (10$\sp4$ receptors/cell) and one with 100% chance (10$\sp6$ receptors/cell). Third, this capture probability estimate is used in the investigation of dual receptor types on autocrine cells. Based on parameter values for the interleukin 2/T-lymphocytes, three potential mechanisms of action for low-affinity receptors are examined: ligand reservoir, receptor reservoir, surface transporter. Both reservoir mechanisms lead to competitive reduction in high-affinity receptor-ligand complexes while surface diffusion allows the competitive binding to be translated into increased signaling complexes. The presence of low-affinity receptors on non-autocrine cells is also examined; their effect on binding of exogenous (paracrine or endocrine) ligands is found to be less influential than it is on binding of autocrine ligand.
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