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03 rencontres biomédicale LIR Xavier Jeunemaitre
1. H E G P Epidemiology, Genetics, Pathophysiology, Experimental Models, Imaging, Human Investigation, Therapeutics Genetics of cardiovascular diseases from rare families to common diseases Xavier Jeunemaitre
2. Rare and common variants in CV diseases MacCarthy , Nature Review Gentetics 2006
3. From rare diseases to the general population Heterozygous FH : 1/500 Homozygous FH : 1/10 6 1964 Rare families with autosomal familial hypercholesterolemia (Khachadurian AK, Am J Med 1964) 1973-1980 The LDL receptor pathway (Brown and Goldstein)
4. From rare diseases to the general population Soutar AK and Naoumova RP (2007) Nat Clin Pract Cardiovasc Med 1985-2000 Discovery of mutations in the LDLR gene 1985 NIH : lowering blood cholesterol as a major national health goal. STATINS
5. From rare diseases to the general population Statin therapy reduce the 5-year incidence of CV events by about 1/5th per mmol/L reduction in LDL cholesterol, irrespective of the initial lipid profile 10 fold increase in the use of statins for prevention of CV diseases 1994-2010
6. From rare diseases to the general population PCSK9 : a new target in the LDL-R pathway
9. Long and Kidney-Specific WNK1 L-WNK1 KS-WNK1 L- and KS-WNK1: Role on Na, K, Cl balance through renal transporters Cl - Na + Cl - NCC WNK4 L-WNK1 KS-WNK1 K + ROMK WNK4 P ENaC Na + L-WNK1 APICAL BASOLATERAL P KS-WNK1 WNK3
10. Long WNK1 Kinase and the arterial wall L-WNK1 E9.5 E17.5 Embryo -/- Adult +/- L-WNK1 : role in vascular development, in arterial myogenic tone 0 2 4 * -8 -6 -4 L-WNK1+/+ L-WNK1+/- LOG PHENYLEPHRINE CONTRACTION (mN) L-WNK1+/+ L-WNK1-/- Tg (WNK1 IL-LacZ) v a aorta Superficial vessels Delaloy C et al., Am J Path 2006
11. RENIN ANGIOTENSIN SYSTEM Angiotensin II Angiotensinogen Angiotensin I Renin Converting enzyme ARB (sartan) ACE Inhibitors AT 2 R Ca ++ PKC Phospholipase C DAG G q IP3 AT2 agonists Anti AT 1 effects Renin Inhibitors Vasoconstriction Aldosterone secretion Proliferation Cardiovascular remodeling AT 1 R
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13. ARGHEF 1 AS A NEW TARGET FOR ANTIHYPERTENSIVE THERAPIES
14. Genetics of CV diseases : from rare families to common diseases Rare forms of cardiovascular diseases can help to identify pathways important for the general physiology In France, a special access to rare families through a unique network of Centres for Rare Diseases and to Clinical Investigation Centres Strong teams working on basic mechanisms underlying cardiovascular diseases
Notas del editor
Presentation of the CV centers in Paris PARCC - genetics
As a proof of concept, a demonstration of the interest of the identification of genes involved in rare forms of disease, familial Hypercholesterolemia and the LDL receptor
A French group opened a new avenue in the field by the discovery of a new target, PCSK9, a protein proconvertase regulating LDL cholesterol metabolism Mutations in families with FH Interestingly, 2 types of mutations exist – gain of function mutations increased LDL, loss-of-function mutation decreased LDL (2% Black population protection against early CHD Clearly, inhibition or repression of PCSK0 expression is a new and important target for the pharmaceutical industry
Simarly to blood cholesterol, regulation of blood pressure is complex 2 examples one from rare disease, one from experimental model