2002 Fiscal Year Final Research Report Summary
Development of molecular pharmacological strategies against oxidant stress-induced steroid resistance
| Project/Area Number |
12670784
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Pediatrics
|
|---|
| Research Institution | Tokyo Women's Medical University |
|---|
Principal Investigator |
YOSHIOKA Toshimasa Tokyo Women's Medical University, School of Medicine, Assoc. Prof., 医学部, 助教授 (60146438)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
SUGANUMA Taiyo Tokyo Women's Medical University, School of Medicine, Instructor, 医学部, 助手 (00328379)
TSUKAHARA Fujiko Tokyo Women's Medical University, School of Medicine, Assoc. Prof., 医学部, 助手 (40119996)
MURAKI Takamura STIGATTokyo Women's Medical University, School of Medicine, Professor, 医学部, 教授 (50051446)
|
|---|
| Project Period (FY) |
2000 – 2002
|
| Keywords | Glucocorticoid / Glucocorticoid receptor / Oxidant stress / Heat shock protein / Free radicals / Nitric oxide / Antioxidants / Estrogen |
|---|
| Research Abstract |
1. Reduced steroid sensitivity in cells exposed to oxidant stress : Using green fluorescent protein-tagged receptor and reporter gene assays, impaired glucocorticoid-dependent nuclear import of receptor and transcriptional activation by oxidant stress was demonstrated. In a separate study, estrogen-dependent transcriptional activation by estrogen receptor-a was found to be also impaired by oxidant stress. Thus, oxidant stress impairs steroid-dependent gene transcription.
2. Role of heat shock proteins (HSPs) in steroid sensitivity : In the model of cellular oxidant stress, an introduction of a member of HSPs, HSC70, restored steroid sensitivity. In vivo model of endotoxin-induced vascular permeability change, induction of HSP70 by heat stress prevented subsequent endotoxin-induced microvascular permeability change in mouse skin. These results indicated molecular pharmacological manipulation to induce HSPs may protect cellular steroid resistance induced by oxidant stress.
3. Mechanisms of free radical production in pathophysiological conditions and applications of antioxidant drugs : As a mechanism of cellular injury in progressive renal disease, some uremic toxins, organic acids, were newly found to induce renal proximal tubular injury by oxidant stress after reabsorbed by the cells vial transporter-medicated uptake. Some antioxidant drugs were found to have nitric oxide scavenging ability. Such effect may modify the pharmacological effect of the drug in specific paphophysiological conditions where nitric oxide and oxygen-derived free radicals co-exist.
|
