توزیع پلیمورفیسمهای ApoE در جمعیت لر

هلاقم تفایرد : 20 / 9 / 92 هلاقم شریذپ ، : 18 / 10 / 92  همدقم : نیئتورپوپیلوپآ E (ApoE) ب فلتخم عاونا هب لاتبا دادعتسا رد يرامی تکراشـم اه راد د . یپیتوـنژ زیلاـنآ هـعلاطم نـیا فدـه ApoE دوب راب نیلوا يارب رل موق رد .  شور و داوم اه : هعلاطم نیا رد 100 یلپ رظن زا رل دنواشیوخریغ ملاس درف مسیفروم ياه ApoE هریجنز شنکاو شور هب رـب زارمیلپ يا یلپ ساسا هدنوش دودحم هعطق لوط مسیفروم (PCR-RFLP) دندیدرگ پیات . یـلپ یـللآ و یپیتوـنژ یناوارف ،تیاهن رد مسـیفروم ياـه ApoE دش هسیاقم یناریا تیعمج اب رل تیعمج رد .  هتفای اه : پیتونژ شش ApoE یلپ مامت و مسیفروم ياه ApoE عمج رد ی دندیدرگ هدهاشم رل ت . پیتونژ ε3/ε3 یـناوارف اـب 48 ٪ عیاش ب رل تیعمج رد پیتونژ نیرت دو . عیاش للآ زین رل تیعمج رد للآ نیرت ε3 دوب .  هجیتن و ثحب يریگ : یلپ یناوارف هک دهد یم ناشن جیاتن مسیفروم ياه ApoE یگژیو ياراد رل تیعمج رد هدـش شرازـگ یلک ياه تیعمج رد یم یناریا یناوارف یخرب شیازفا ای شهاک اب یلو ،دشاب نم مه زونه ،اه تسا درف هب رصح .  هژاو يدیلک ياه : نیئتورپوپیلوپآ E یلپ ، ناریا ،رل تیعمج ،مسیفروم . هدیکچ


Scientific Profile of the Apoe Targeted Mutation Mouse Model
Apoe Targeted Mutation Mice are homozygous for a defective Apoe gene, and apoE protein is absent from blood of these animals. 1 Plasma lipoproteins in which apoE normally is an integral part (e.g., VLDL, IDL, HDL) are therefore devoid of this apolipoprotein. 2As a result, Apoe Targeted Mutation Mice show dramatic alterations in lipid metabolism and transport, even on a normal mouse chow diet.
In normal mice, the protein apoE is made predominantly by the liver (as in humans) and becomes incorporated into all lipoprotein particles (except LDL), including those constructed by intestinal cells (chylomicrons) for transport of ingested lipids through the bloodstream, and those constructed by liver cells to distribute lipids via the circulation and fuel cellular metabolism during fasting (VLDLs). 3poE is present in other lipoprotein particles that are metabolic products (IDLs, chylomicron remnants), or those involved in acquisition of cholesterol from tissues and reverse cholesterol transport (HDLs).
The most well-documented function of apoE is to facilitate binding of lipoproteins to cell surface receptors, thereby enhancing transfer of components of the particle's lipid moeity (e.g., cholesteryl esters, triacyl-glycerols) to or from cells.Specifically, apoE mediates binding to both LDL and LRP (LDL receptor-related protein) receptors, and possibly the VLDL receptor. 4Less well understood but intriguing are possible roles for apoE in nerve regeneration and amyloid processing in CNS neurons.

The absence of apoE has multiple effects on lipid metabolism and transport.
In normal mice, the profile of cholesterol-containing plasma lipoproteins includes an abundance of high density lipoprotein (HDL) and only trace amounts of lower-density lipoproteins (VLDL, IDL, LDL). 2,3In contrast, Apoe Targeted Mutation Mice have the reverse distribution: 80% of serum cholesterol is sequestered in lower density lipoproteins, while HDL-cholesterol is half the normal level. 2n addition, total cholesterol levels in plasma of Apoe Targeted Mutation mice are up to five times that of normal mice (e.g., 434 mg/dl versus 86 mg/dl, respectively). 2 Thus, both the quantity of cholesterol and its distribution among lipoprotein fractions are shifted in the mutant mice to a pattern known to be associated in humans with risk of atherosclerosis.

Targeted
Mutation Mice confer a spontaneous susceptibility to early and extensive development of atheromas regardless of diet.Unlike normal mice, which do not develop atherosclerotic lesions (except for some strains on high fat/high cholesterol diets), Apoe Targeted Mutation Mice fed normal mouse chow develop foam cell accumulations on their aortic walls by 3 months of age, which progress to extensive atherosclerotic lesions and severe vessel occlusion by 8 months. 2her than lipid alterations and propensity to develop atherosclerosis, Apoe Targeted Mutation Mice are of similar weight to normal mice and appear otherwise healthy. 2 This, combined with early atherosclerosis and underlying changes in plasma lipid profile that mimic the human atherogenic profile, make Apoe Targeted Mutation Mice an ideal model for human atherogenesis.They also can serve as a model for human apoE deficiency, a rare genetic disorder.

The apoE deficiency has been corrected experimentally in Apoe Targeted Mutation
Mice, with a return to normal lipoprotein distribution and cholesterol levels (650 mg/dl in apoE deficient mice versus 100-150 mg/dl in apoE corrected mice). 4This was accomplished by gene replacement through infusion of an adenovirus vector containing the human Apoe gene, and resulted in mice with markedly reduced incidence of atherosclerosis.

Origin of the Model
The Apoe Targeted Mutation Mouse Model was developed by Nobuyo Maeda and colleagues at the University of North Carolina in Chapel Hill. 1 Inactivation of the Apoe gene was accomplished by homologous recombination, by electroporation of cultured E14TG2a cells with a plasmid that contains a modification of the murine Apoe locus, in which a portion of the normal Apoe gene sequence had been replaced by neomycin-resistance and thymidine kinase marker genes.
Electroporated cells that had undergone successful recombination of wild-type and plasmid-derived Apoe gene sequences were identified by positive neomycin resistance, and hence, presence of the disrupted Apoe gene.Chimeric mice then were generated by injecting such cells into blastocysts of C57BL/6J mice.
Of the mice that developed from the blastocysts, a male chimera (JH126.1)was found to transmit the embryonic cell genome to 100% of his offspring in a backcross to a C57BL/6 female.The resulting pups inherited the Apoe gene in expected Mendelian proportion (50%), indicating integration of the mutation into the genome and no effect of the mutation on embryo viability.
The mice were transferred to Taconic in May 1998 after ten backcrosses (N10) to C57BL/6J from the (129 X C57BL/6) chimera and intracrossing to homozygosity.The line was then further backcrossed at Taconic to C57BL/6N (N11) and derived by embryo transfer.The colony is maintained at N11 through intercrossing of homozygous mice.

Ready for Your Experiments
Taconic's Apoe targeted mutation mice are produced in Isolator Barrier Unit (IBU TM ) facilities.
Mice are shipped in Taconic Transport Cages (TTC TM ) and come with an upto-date health report documenting their Murine Pathogen Free (MPF TM ) health status.Barrier housing conditions are recommended for maintenance of Apoe Targeted Mutation homozygous mice.

Related Mouse Models from Taconic
Taconic provides a number of mouse models relevant to lipoprotein metabolism and atherogenesis.Call, fax, or visit Taconic's website for information about these additional models: • ApoB100 Microinjected Mouse (model 001004) -develops atherosclerosis on a high fat/high cholesterol diet, due to expression of high levels of human apolipoprotein B100 and a resultant elevated plasma cholesterol (total and LDLassociated).  .4,873,191; 4,740,470;  5,464,764; 5,487,992; 5,627,059; 5,631,153; 5,789,215; and  6,204,061.
Every Taconic Transgenic Model™ carries a label license granting you a license under Taconic's in-licensed patent right(s) to use the model in your research.TTM™s are produced and distributed under rights to patents that Taconic has licensed from various institutions, including exclusive distribution rights to Positive Negative Selection and Isogenic DNA gene targeting technologies.Taconic is the only commercial breeder that can supply transgenic models with these licenses for use in your research.

Conditions of Use for Taconic Transgenic Models™
TACONIC TRANSGENIC MODELS™ ("MODELS") are produced and distributed under rights to patents and intellectual property licensed from various institutions.Taconic grants to each purchaser a right under Taconic's rights in such licensed patents and intellectual property to use the purchased MODEL in consideration of purchasers' acknowledgement of and agreement to the Terms and Conditions of Sale and the following terms of use: Title to these MODELS and biological materials derived from them remains WITH TACONIC FARMS, INC.The MODELS will be used for research purposes only.
The MODELS will not be bred except to obtain embryos or fetuses required for research purposes.
The MODELS and biological materials derived from them will not be distributed to third parties or used for commercial purposes.
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• 2 •Figure 1 .
Figure 1.Reprinted with permission from the Journal of Clinical Investigation.Kashyap, et al. 4 • APOE2 Targeted Replacement Mouse (model 001547) -expressing the human apoE2 protein instead of murine apoE, with several abnormalities of lipid physiology, including elevated serum levels, altered lipoprotein profiles, and early development of atherosclerosis, all of which parallel features of human type III lipoproteinemia.• APOE3 Targeted Replacement Mouse (model 001548) -expressing the human apoE3 protein instead of murine apoE, with normal serum cholesterol and triglyceride levels, but certain abnormalities of lipid physiology, including delayed clearance of lipoprotein particles (VLDL) and propensity to develop atherosclerosis on a high-fat diet.• APOE4 Targeted Replacement Mouse (model 001549) -expressing the human apoE4 protein instead of murine apoE, with normal serum cholesterol and triglyceride levels but certain abnormalities of lipid physiology that are similar to those of ApoE3 Targeted Replacement Mice; impairment in clearance of lipoprotein particles (VLDL) and development of atherosclerosis on a high-fat diet are more pronounced.• CETP Microinjected Mouse (model 001003) -expressing human cholesteryl ester transfer protein, a plasma enzyme normally absent in mice, which in humans mediates HDL-cholesterol transfer to VLDL and LDL and enhances cholesterol uptake into cells; transgenic mice have dramatically reduced HDL-cholesterol.• CETP/ApoB100 Double Microinjected Mouse (model 001007) -develops atherosclerosis rapidly on a high-fat/highcholesterol diet or normal mouse chow after six months, due to expression of both human CETP and apoB100 and consequent alterations in plasmalipid profile (elevated LDL-cholesterol, reduced HDL-cholesterol) 4. Kashyap V.S., Santamarina-Fojo S., Brown D.R., Parrott C.L., Applebaum-Bowden D., Meyn S., Talley G., Paigen B., Maeda N., Brewer, Jr., H.B. (1995) Apolipoprotein E Deficiency in Mice: Gene Replacement and Prevention of Atherosclerosis Using Adenovirus Vectors.Journal of Clinical Investigation, Vol.96, pp.1612-1620.© Copyright 2008, Taconic Farms, Inc. RG290495 TACONIC TRANSGENIC MODELS are produced and distributed under rights to patents and intellectual property licensed from various institutions.Transgenic Models are produced and distributed under United States Patent Nos 2