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--- home:publications:marshall_days_of_molecular_medicine_2007 [09.03.2010] – external 127.0.0.1
+++ home:publications:marshall_days_of_molecular_medicine_2007 [09.05.2010] – paulalbert
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- ====== Poster - Bacteria induced vitamin D receptor dysfunction in autoimmune disease: theoretical and practical implications for interpretation of serum vitamin D metabolite levels ======
+~~NOTOC~~
+====== Poster - Molecular static and dynamic analyses reveal flaw in murine model used by US FDA to detect drug carcinogenicity ======
-**Type:** Poster presentation\\
+**Type:** Abstract presentation\\
-**Presenter:**  Trevor Marshall PhD\\
+**Presented by:**  Trevor Marshall, PhD\\
-**Conference:**  [[http://www.nature.com/nm/meetings/dmm2007/program.html/|Days of Molecular Medicine 2007]]\\
+**Conference:**  [[http://www.nature.com/nm/meetings/dmm2007/program.html|Days of Molecular Medicine 2007]]\\
 **Location:**  Harvard University\\
-**Date:**  May 22-24, 2007\\
+**Date:**  2007\\
-**Additional content:** [[http://autoimmunityresearch.org/transcripts/dmm2007-harvard.pdf|abstract]]; [[http://autoimmunityresearch.org/dmm2007/dmm2007.ram|video showing difference in steady-state ligand conformation between rat and human VDR]]
+**Additional content:** [[http://autoimmunityresearch.org/transcripts/dmm2007-harvard.pdf|poster]]; [[http://autoimmunityresearch.org/dmm2007/dmm2007.ram|video showing difference in steady-state ligand conformation between rat and human VDR]]
 ===== Abstract =====
-The US FDA currently accepts carcinogenicity studies of 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:
-http://www.fda.gov/cder/foi/nda/2002/21-286_Benicar.htm)), possible carcinogenicity observed in hamsters was not 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
+The US FDA currently accepts carcinogenicity studies of
-Chronic Inflammatory and Autoimmune Disease. Abstract presentation, DMM2006.)), while it has antagonistic activity in 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 (1,25-dihydroxyvitamin-D). Since the VDR is believed to express 913 genes(({{pubmed>long:16002434}})), many of which are known to be associated with cancer pathogenesis, good homology between human VDR, and the animal model VDR, is exceedingly important.
+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://www.fda.gov/cder/foi/nda/2002/21-286_Benicar.htm)), possible carcinogenicity observed in hamsters was not
+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 presentation, DMM2006.)), while it has antagonistic activity in
+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 (1,25-dihydroxyvitamin-D).
+Since the VDR is believed to express 913 genes(({{pubmed>long:16002434}}))
+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://autoimmunityresearch.org/dmm2007/dmm2007.ram, many of which are
+known to be associated with cancer pathogenesis, good homology
+between human VDR, and the animal model VDR, is exceedingly
+important.
 ==== Conclusion ====
-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>posters Trevor_Marshall_PhD DMM 2007 vitamin_d animal_models}}
+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>posters Trevor_Marshall_PhD DMM 2007}}
 ===== References =====

home/publications/marshall_days_of_molecular_medicine_2007.txt · Last modified: 09.14.2022 by 127.0.0.1