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Polymophism in the promoter


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SHAPE Society

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Polymophism in the promoter

  1. 1. G(-670)-> A. polymophism in the promoter of the fas gene is a riskG(-670)-> A. polymophism in the promoter of the fas gene is a risk factor for myocardial infarction --Miyuki Onishi et al.factor for myocardial infarction --Miyuki Onishi et al.  Fas is a receptor that mediates apoptosis which is a critical event for eliminating activated macrophages.  Method:  154 subject with recent MI, 462 control.  Fas expression was detected on peripheral blood mononuclear cells.  Results: A/G polymorphism of the fas gene significantly different between MI and controls. Leukemia inhibitory factor significantly suppressed the levels of Fas expression in AA genotype subjects, no effect in subjects with GG genotype.  Conclusion: The A allele of G/A polymorphysm in the promoter region (-670-A) of the Fas gene is a new genetic risk factor of MI via modulation of Fas expression
  2. 2. Immunoglobulin Treatment Suppresses AtherosclerosisImmunoglobulin Treatment Suppresses Atherosclerosis in Apolipoprotein E Knockout Mice via the FC portionin Apolipoprotein E Knockout Mice via the FC portion --Zhuyi Yuan et al--Zhuyi Yuan et al  IG is used for the treatment of immune-mediated disease.  Method: ApoE mice fed with high fat diet. IP injection of Human IG or F(ab’)2 fragments of IG at 8 weeks and 16 weeks  Results: IG markedly suppressed Fatty streak formation and fibofatty plaque and macrophage accumulation F(ab’)2 has no effect.  Conclusion: IG therapy markedly suppressed atherosclerosis via the Fc portion of IG. The suppression is associated with marked reduction of macrophage density in the region.
  3. 3. NF-kB Inhibition Reduces Pro-Inflammatory Molecule ExpressionNF-kB Inhibition Reduces Pro-Inflammatory Molecule Expression and Attenuates Atherosclerosis in ApoE-/- miceand Attenuates Atherosclerosis in ApoE-/- mice Yutaka Furukawa et al.Yutaka Furukawa et al.  Activation of NF-kB induces pro-inflammatory molecule mRNA including MCP-1 and VCAM-1.  Method: NF-KP inhibitor(NF-kB1) was used. Male C57BL/6 apoE-/- mice were fed a western type diet. Administ. Of NF-kB1 or vehicle for 10 weeks.  Results: Immunohistochemistry: macrophage accumulation and VCAM-1 expression attenuated. Real-time PCR showed that VCAM-1 and MCP-1 mRNA expression in the aorta decreased  Conclution: NF-kB may be a therapeutic target in the prevention of atherosclerosis.
  4. 4. Cholesterol Regulated Genome wide approchCholesterol Regulated Genome wide approch BreslowBreslow Using microarray to identify genes regulated by dietary cholesterol in the mouse live. Method: C57BL/6J mice W/o cholestrol With 0.5% cholesterol. Pooled or individual hybridize with array. Retain genes with signal > 250, Fold>1.6. Unigen cluster tools, got 88 probe set * There are 15 starts in Human Genome. He introduced Star D4,5,6 from the probe set. •PNAS (2002)99:6949- 6954 •JBC(2002)276:4261 •Biochemistry(2000)39:153 99 •Science 290:1712 •Proteins(2001)43:134
  5. 5. MMP-8: Evidence of a New Collagenolytic Pathway in AcuteMMP-8: Evidence of a New Collagenolytic Pathway in Acute Plaque DisruptionPlaque Disruption Lan Loftus et al.Lan Loftus et al.  MMP-8 is the enzyme that preferentially degrades type I collagen.  Aim: quantify the level of MMP-8 in carotid plaques.  Method: Plaque from 75 patients undergoing carotid endarterectomy. MMP-8 level were quantified using ELISA.Immunostaining. All patient undergo Td monitoring to detect spontaneous embolisation.  Results: MMP-8 level in plaque higher in patients with recent symptoms and spontaneous embolisation. There is significant relation between level of MMP-8 and MMP-9.  Conclusion: Elevate of MMP-8 and together with MMP-9 have the potential to degrade all components of extracellular matrix and represent a target for pharmacotherapy to prevent acute plaque disruption.
  6. 6. Enhanced Migration and Matrix Degradation by ChlamydiaEnhanced Migration and Matrix Degradation by Chlamydia pneumoniae-Infected Monocytes via the plasminogen andpneumoniae-Infected Monocytes via the plasminogen and EMMPRIN/MMP Activation system. Implications for PlaqueEMMPRIN/MMP Activation system. Implications for Plaque Rupture. -- Roland Schmidt et al.Rupture. -- Roland Schmidt et al.  The effects of initiation of matrix degrading activity in monocytes with regard to the role of EMMPRIN, Extracellular MMP- inducer.  Method and results: MonoMac6 cells or isolated monocytes with C pn for 48 hrs. MMP-2MMP-9,uPAR,membrand-type-1-MMP,EMMPRIN expression enhanced Conclusion: Induces monocytic matrix degradation and matrix invasion via activation of the plasminogen and the EMMPRIN/MMP activative system. Which may contribute to the development of cardiovascular complications such as plaque rupture.
  7. 7. Angiotensin II mediates production of Matrix Metalloproteinases-1Angiotensin II mediates production of Matrix Metalloproteinases-1 and –9 by Monocytes: Implication for Atherosclerotic Plaqueand –9 by Monocytes: Implication for Atherosclerotic Plaque Rupture – Min P Kim et al.Rupture – Min P Kim et al.  Hypothesis: AngII enhances the production of monocyte MMP-1 and MMP-9, two major MMPs associated with plaque rupture.  Method: Elutration of human primary blood monocytes cultured with various agents. Levels of MMP-2,MMP-9 in supernatant were determined by ELISA or western analysis.  Conclusion: AngII has a central role in the production of MMP-1 and MMP-9 by monocytes. It provide insight into the association between hypertension and acut coronary sydrome and a possible mechanism by which angiotensin converting enzyme inhibitor and aspirin may reduce the risk for heart attacks.
  8. 8. Organization of HUPO and opportunity for proteomic research on aOrganization of HUPO and opportunity for proteomic research on a globe wide level as well as in the USAglobe wide level as well as in the USA –Sam Hanash–Sam Hanash Why proteomics: High dynamic compartment Most direct relevant to function High relevant to biological fluid Regulated at transcriptional level and post-transcription level. Field of Proteomics Expression protein Structure protein Protein function Proteomic informatics Goal: Comprehensive analyze of all of protein constituents of a cell or tissue. Tracking of protein traffic. Tracking of post-translational modifiers Types of Technology: Separation Basic: 2D/Mass spec. *present focus on subcellular compartment. Exp: Cell surface protein which is important for diagnostics and therapeutics Tag cell surface protein with Biotin. Then solubolize cell membrane. Run this cell lysate through Avidin column to capture Biotin related cell surface protein. Load onto 2D gel for protein separation. Digest all interest band and identify them with Mass. Combination of electrophoresis and chromatography to fractionate one lysate into a lot of protein. Protein microarray: Identify antigen in autoimmunity. Identify drug binging protein. Studies of protein interaction International cooperation: 1. Reesources and tech. 2. Model cells. 3. Plasma proteomic 4. Informatics. Model cells and tissure: Liver proteomic Heart proteomic Brain proteomic Plasma proteomic.
  9. 9. Gene Expression Profiles during Human Atherogeeneesis; A RoleGene Expression Profiles during Human Atherogeeneesis; A Role for the LIF-Receptor in Lesion Progression --Birgit Faber et alfor the LIF-Receptor in Lesion Progression --Birgit Faber et al  Study: profle large-scale expression on early, advanced but stable and ruptured atherosclerotic plaques.  Method and results: 1. 3 early stage plaque and 3 ruptured plaque mRNA -> run on microarray ( Incyte Genomics Inc) -> 105 gene upregulated and 88 genes down regulated, phase of atherogenesis vs. stable plaques. 79 gene up and 65 gene down after plaque rupture. 2. Hybridize CDNA of (Pooled n=3 for each) normal artery, early lesions, stable lesions and rupture lesion with custome made cDNA expression array. LIF receptor enhanced in plaque rupture. RT-PCR revealed LIF receptor MRNA expression in 1/3 normal arteries, ¼ early leesions,8/10ruptured plaque specimens. LIP receptor protein expression located in smooth muscle cells and macrophages of atherosclerotic lesions.  Conclusion: This expression profile suggests a role for the LIF-receptor in the progression of human atherosclerosis.
  10. 10. Cyr61(CNN1) and Connective Tissue Growth Factor(CNN2) areCyr61(CNN1) and Connective Tissue Growth Factor(CNN2) are Novel Ligands of Inteegrin aMB2 on Peeripheral Blood MonocytesNovel Ligands of Inteegrin aMB2 on Peeripheral Blood Monocytes -- Joseph M Schober et al.-- Joseph M Schober et al.  Cysteine-rich 61(Cry61,CCN1) and connective tissuee growth factor(CTGF, CVN2) are growth factor-incucible immediate- early gene products found in atherosclerotic lesions, restenosed blood vellel walls and healing cutaneous wounds.  Study: Examinee monocyte interaction with Cyr61 and CTGF. Because monocyte adhesion and transmigration are important for athereosclerosis, inflammation and wound healing.  Results: monocyte adhesion to Cyr61 is specificaly blocked by antibodies directed against the integrin aM and B2 subunit indicating that integrin serves as an adhesion recptor on monocyte for thesee CCN protein. Monocyte adhesion to Cyr61 induces the expression of inflammatory mediators including IL-1, IL-8 MCP-1,MRP8 and MRP14.  Suggestion: these finding indicated that Cyr61 and CTGF aree novel ligands of integrin aMB2 on monocytes and suggestion an important pathophysiologic role of monocyte adhesion to CNN protein.