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Leveraging Cell Micropatterning Technology for Rapid Cell-Based Assessment of Chemical Toxicity and Population Variation in Toxicity Susceptibility
Başlık:
Leveraging Cell Micropatterning Technology for Rapid Cell-Based Assessment of Chemical Toxicity and Population Variation in Toxicity Susceptibility
Yazar:
Ngo, Le Phuong, author.
Yazar Ek Girişi:
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Bevin P. Engelward.
Özet:
The massive libraries of existing chemicals coupled with the unprecedented rate of new chemical generation presents a unique and costly challenge to toxicity testing in the 21st century. In recent years, the United States has seen large coordinated efforts across governmental agencies to shift from expensive and slow traditional in vivo tests to more affordable and higher throughput in vitro methods.
Unrepaired DNA damage can lead to deleterious health consequences, including cancer and aging. In this work, we developed and validated a CometChip platform that addresses two major areas that are lacking in genotoxicity testing: 1. rapid and sensitive detection of bulky DNA adducts, and 2. robust and physiologically relevant metabolism. The assay uses two DNA repair synthesis inhibitors to cause strand-break accumulation and HepaRG(TM) cells to provide high levels of liver-specific functions.
In vitro measurements of cell survival after a toxic exposure are among the most broadly used endpoints in biology. The gold standard test is the colony forming assay, which sees limited uses due its low-throughput nature and requirement of large dishes. To overcome these limitations, we have developed MicroColonyChip, which is based on the use of a microcolony array where the size distributions for different conditions provide a direct measure of cell survival. We show here that MicroColonyChip is as sensitive as the gold standard, reduces ~80% incubation time, and requires ~250x less cell growth area.
In addition to detecting genotoxic agents, it is also important to understand how an individual responds to DNA damage as a necessary first step for assessment of human health outcomes. We applied CometChip to study the kinetics of the repair of different types of DNA damage in human primary lymphocytes. Isolated lymphocytes from 56 healthy individuals show significant differences in repair kinetics of oxidative damage and a sevenfold variation in repair rates.
Taken together, the work described here represents significant technological advances in addressing a number of major challenges in chemical toxicity testing as well as in the evaluation of health outcome variability across populations. The technologies also open doors to exciting opportunities in personalized strategies for disease prevention and intervention. (Copies available exclusively from MIT Libraries, libraries.mit.edu/docs - docs mit.edu).
Notlar:
School code: 0753
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
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