Browsing by Subject "Sensitivity Analysis"
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Item Use of Systems Engineering Approaches To Examine Stability & Sensitivity Of Alzheimer's Associated Pathways(2016-01-01) Agarwal, Neil Tushar; Good, Theresa A; Chemical, Biochemical & Environmental Engineering; Engineering, Chemical and BiochemicalAlzheimer'sdisease (AD) is a progressive neurodegenerative disorder that affects the elderly population. There are two histopathological hallmarks of AD, the formation of neurofibrillary tangles, and amyloid plaques. The primary protein component of senile plaques is beta amyloid (Aβ), a 39 to 43 amino acid long peptide, which investigators believe plays a causative role in AD. At a molecular level, it appears that Aβ impacts complex signaling networks that contain a substantial degree of signal integration. To date, most investigators have examined the influence of Aβ by investigating one signaling pathway at a time. In this work, a systems engineering approach is taken to examine how much Aβ influences the stability and sensitivity to change of biological parameters, and discuss the possible biological interpretations in a complex reaction network. The simplified model did not capture expected trends. Viability and death signals were insensitive to the amount of ECM and Aβ, although the output was sensitive to the rate constant associated with matrix-integrin interaction. Our more complex model did capture expected salient trends with respect to the viability signal. Furthermore, the model displayed asymptotic stability at high and low viability signal in the absence and presence of Aβ respectively. Sensitivity to parameter interactions associated with Aβ were observed, that could be related to experimental toxicity attenuation data. The work demonstrates the utility of such tools in analyzing reaction networks. The tools can relate model parameters with experimental findings, with improved predictions, that help identify therapeutic avenues for altering neurotoxicity associated with Aβ.