دورية أكاديمية
Feedback control of protein aggregation.
| العنوان: | Feedback control of protein aggregation. |
|---|---|
| المؤلفون: | Dear AJ; School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA., Michaels TCT; School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA., Knowles TPJ; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom., Mahadevan L; School of Engineering and Applied Sciences, Department of Physics, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA. |
| المصدر: | The Journal of chemical physics [J Chem Phys] 2021 Aug 14; Vol. 155 (6), pp. 064102. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Institute of Physics Country of Publication: United States NLM ID: 0375360 Publication Model: Print Cited Medium: Internet ISSN: 1089-7690 (Electronic) Linking ISSN: 00219606 NLM ISO Abbreviation: J Chem Phys Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: New York, NY : American Institute of Physics Original Publication: Lancaster, Pa., American Institute of Physics. |
| مواضيع طبية MeSH: | Amyloid/*antagonists & inhibitors, Amyloid/metabolism ; Feedback ; Humans ; Kinetics ; Protein Aggregates/drug effects ; Stochastic Processes |
| مستخلص: | The self-assembly of peptides and proteins into amyloid fibrils plays a causative role in a wide range of increasingly common and currently incurable diseases. The molecular mechanisms underlying this process have recently been discovered, prompting the development of drugs that inhibit specific reaction steps as possible treatments for some of these disorders. A crucial part of treatment design is to determine how much drug to give and when to give it, informed by its efficacy and intrinsic toxicity. Since amyloid formation does not proceed at the same pace in different individuals, it is also important that treatment design is informed by local measurements of the extent of protein aggregation. Here, we use stochastic optimal control theory to determine treatment regimens for inhibitory drugs targeting several key reaction steps in protein aggregation, explicitly taking into account variability in the reaction kinetics. We demonstrate how these regimens may be updated "on the fly" as new measurements of the protein aggregate concentration become available, in principle, enabling treatments to be tailored to the individual. We find that treatment timing, duration, and drug dosage all depend strongly on the particular reaction step being targeted. Moreover, for some kinds of inhibitory drugs, the optimal regimen exhibits high sensitivity to stochastic fluctuations. Feedback controls tailored to the individual may therefore substantially increase the effectiveness of future treatments. |
| المشرفين على المادة: | 0 (Amyloid) 0 (Protein Aggregates) |
| تواريخ الأحداث: | Date Created: 20210815 Date Completed: 20210830 Latest Revision: 20210830 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1063/5.0055925 |
| PMID: | 34391352 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Scitation. | تدمد: | 1089-7690 |
|---|---|
| DOI: | 10.1063/5.0055925 |