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home:publications:marshall_days_of_molecular_medicine_2006 [09.05.2010] – paulalbert | home:publications:marshall_days_of_molecular_medicine_2006 [07.04.2022] (current) – external edit 127.0.0.1 | ||
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- | ====== Poster - Molecular static and dynamic analyses reveal flaw in murine model used by US FDA to detect drug carcinogenicity | + | ====== Poster - VDR Nuclear Receptor competence is the key to recovery from chronic inflammatory and autoimmune disease |
**Type:** Abstract presentation\\ | **Type:** Abstract presentation\\ | ||
**Presented by:** Trevor Marshall, PhD\\ | **Presented by:** Trevor Marshall, PhD\\ | ||
- | **Conference: | + | **Conference: |
- | **Location: | + | **Location: |
- | **Date: | + | **Date: |
- | **Additional content:** [[http:// | + | **Additional content:** [[https:// |
- | ===== Abstract ===== | + | |
- | The US FDA currently accepts carcinogenicity studies of | + | ===== Abstract |
- | pharmaceutical drugs based on murine models. In addition to 6 month | + | |
- | studies with p53(+/-) and ras.H2 transgenic mice, lifetime studies | + | |
- | (typically 2 years) in WT mice or rats are also considered as evidence | + | |
- | that a drug lacks carcinogenic activity. This model is not always | + | |
- | exhaustive. For example, during the acceptance testing of the ARB | + | |
- | Olmesartan((FDA CDER: NDA-21-286, Sankyo Pharma Inc Available from URL | + | |
- | http:// | + | |
- | able to be duplicated in rats, or in transgenic mice. We have previously | + | |
- | used the static molecular modeling of AutoDock to demonstrate that | + | |
- | Olmesartan has agonostic activity in the PDB:1DB1 model of the | + | |
- | human VDR Nuclear Receptor((Marshall TG: VDR Nuclear Receptor Competence is the Key to Recovery from | + | |
- | Chronic Inflammatory and Autoimmune Disease. | + | |
- | Abstract | + | |
- | the PDB:1RK3 model of the rat VDR. This agonism has now been | + | |
- | confirmed with Molecular Dynamics, using GROMACS. The murine | + | |
- | VDR indeed lost its ability to bind the DRIP 205 co activator when | + | |
- | Olmesartan was the ligand, while the human VDR was activated by | + | |
- | Olmesartan similarly to its native ligand (1, | + | |
- | Since the VDR is believed to express 913 genes(({{pubmed> | + | |
- | This video was created using the GROMACS Molecular | + | |
- | Dynamics software on a small computing cluster assembled | + | |
- | from PCs based on Core-2-duo CPU technologies. The | + | |
- | difference in steady-state ligand conformation between | + | |
- | human and rat VDR can clearly be seen at | + | |
- | http:// | + | |
- | known to be associated with cancer pathogenesis, | + | |
- | between human VDR, and the animal model VDR, is exceedingly | + | |
- | important. | + | |
- | ==== Conclusion ==== | + | The VDR Nuclear Receptor is at the heart of the human innate immunity, responsible for TLR2, TLR4, CAMP TACO and IL2 expression [1]. During Th1 immune challenge, the VDR is activated by the endogenous secosteroid 1,25 dihydroxyvitamin D. We have previously described how intra-phagocytic bacterial pathogens are responsible for much chronic inflammatory disease [2,3], and our phase 2 study results have confirmed this pathogenesis. In order to induce recovery from chronic inflammatory disease, it is necessary to restore VDR function by removing all exogenous sources of the secosteroid we call ‘Vitamin-D, |
+ | RESULTS: To date we have demonstrated recovery from Hashimoto’s Thyroiditis, | ||
- | The murine environment is inadequate to accurately | ||
- | model drug carcinogenic activity in humans. A species should be | ||
- | chosen which has a VDR LBP homology closer to that of man. AutoDock | ||
- | and GROMACS molecular analyses are useful in resolving any | ||
- | remaining anomalies in the observed data. | ||
- | {{tag> | ||
- | ===== References ===== | ||
- | {{tag> | + | {{tag> |