Greg bitgood veterinarian
This application is a continuation of and claims priority of Ser. Low HDL cholesterol HDL-Cor hypoalphalipoproteinemia, is a blood greg bitgood veterinarian abnormality which correlates with a high risk of cardiovascular disease CVDin particular coronary artery disease CADbut also cerebrovascular disease, coronary restenosis, and peripheral vascular disease. HDL-C levels are a strong graded and independent cardiovascular risk factor.
Protective effects of an elevated HDL-C persist until 80 years of age. Furthermore, it has been shown that even within high risk populations, such as those with familial hypercholesterolemia, HDL cholesterol level is an important predictor greg bitgood veterinarian CAD.
These findings have led to increased attention to HDL cholesterol levels as a focus greg bitgood veterinarian treatment, following the recommendations of the National Cholesterol Education Program.
These guidelines suggest that HDL cholesterol values below 0. It is greg bitgood veterinarian crucial that we obtain a better understanding of factors which contribute to this phenotype. In view of the fact that pharmacological intervention of low HDL cholesterol levels has so far proven unsatisfactory, it is also important to understand the factors that regulate these levels in the circulation as greg bitgood veterinarian understanding may reveal new therapeutic targets.
What seems to be important in this case is the functional activity of the reverse cholesterol transport pathway, the process by which intracellular cholesterol is trafficked greg bitgood veterinarian of the cell to acceptor proteins such as ApoAI or HDL.
Other important genetic determinants of HDL cholesterol levels, and its inverse relation greg bitgood veterinarian CAD, may reside in the processes leading to HDL formation and intracellular cholesterol trafficking and efflux.
To greg bitgood veterinarian, this process is poorly understood, however, and clearly not all of the components of this pathway have been identified. Therefore it is critical to identify and understand novel genes involved in the intracellular cholesterol trafficking and efflux pathways. HDL particles are central to the process of reverse cholesterol transport and thus to the greg bitgood veterinarian of tissue cholesterol homeostasis.
This process has multiple steps which include the binding of HDL to cell surface components, greg bitgood veterinarian acquisition of cholesterol by passive absorption, the esterification of greg bitgood veterinarian cholesterol by LCAT and the subsequent transfer of esterified cholesterol by CETP, to VLDL and chylomicron remnants for liver uptake.
Each of these steps is known to impact the plasma concentration of HDL. TD patients accumulate cholesterol esters in several tissues, resulting in characteristic features, such as enlarged yellow tonsils, hepatosplenomegaly, peripheral neuropathy, and cholesterol ester deposition in the rectal mucosa. Defective removal greg bitgood veterinarian cellular cholesterol and phospholipids by ApoAI as well as a marked deficiency in HDL mediated efflux of intracellular cholesterol has been demonstrated in TD fibroblasts.
Even though this is a rare disorder, defining its molecular basis could identify pathways relevant for cholesterol regulation in the general population. The decreased availability of free cholesterol for efflux in the surface membranes of cells in Tangier Disease patients appears to be due to a defect in cellular lipid metabolism or trafficking. As increased cholesterol is observed in the rectal mucosa of persons with TD, the molecular mechanism responsible for TD may also regulate cholesterol adsorption from the gastrointestinal GI tract.
A more common form of genetic HDL deficiency occurs in patients who have low plasma HDL cholesterol usually below the 5th percentile for age and sex OMIMbut an absence of clinical manifestations specific to Tangier disease Marcil et al. These patients have no obvious environmental factors associated with this lipid phenotype, and do not have severe hypertriglyceridemia nor have known causes of severe HDL deficiency mutations in ApoAI, LCAT, or LPL deficiency and are not diabetic.
The pattern of inheritance of this condition is most consistent with a Mendelian dominant trait OMIM The development of drugs that regulate cholesterol metabolism has so far progressed slowly. Thus, there greg bitgood veterinarian a need for a better understanding of the genetic components of the cholesterol efflux pathway.
Newly-discovered components can then serve as targets for drug design. Low HDL levels are likely to be due to multiple genetic factors. The use of greg bitgood veterinarian in the aid of designing treatment tailored to the patient makes it desirable to identify polymorphisms in components of the cholesterol efflux pathway.
Greg bitgood veterinarian understanding greg bitgood veterinarian the effect of these polymorphisms on protein function would allow for the design of a therapy that is optimal for the patient.
Specifically excluded from the polypeptides of the invention are the polypeptide having the exact amino acid sequence as GenBank accession number CAA Also excluded is protein having the exact amino acid sequence as GenBank accession number X In another aspect, the invention features a substantially pure nucleic acid molecule encoding an ABC1 polypeptide having ABC1 biological activity e.
In a related aspect, the invention features an expression vector, a cell, or a non-human mammal that includes the nucleic acid molecule greg bitgood veterinarian the invention. In yet another aspect, the invention features a substantially pure nucleic acid molecule that includes nucleotides 75 to of SEQ ID NO: In a related aspect, the invention features a substantially pure greg bitgood veterinarian acid molecule that hybridizes at high stringency to a probe comprising nucleotides of SEQ ID NO: In another aspect, the invention features a method of treating a human having low HDL cholesterol or a cardiovascular disease, including administering to the human an ABC1 polypeptide, or cholesterol-regulating fragment thereof, or a greg bitgood veterinarian acid molecule encoding an ABC1 polypeptide, or cholesterol-regulating fragment thereof.
In a preferred embodiment, the human has a low HDL cholesterol level relative to normal. Preferably, the ABC1 polypeptide is wild-type ABC1, or has a mutation that increases its stability or its biological activity. A preferred biological activity is regulation of cholesterol. In a related aspect, the invention features a method of preventing or treating cardiovascular disease, including introducing into a human an expression vector comprising an ABC1 nucleic acid molecule operably linked to a promoter and encoding an ABC1 polypeptide having ABC1 biological activity.
In another related aspect, the invention features a method of preventing or ameliorating the effects of a disease-causing mutation in an ABC1 gene, including introducing into a human an expression vector comprising an ABC1 nucleic acid molecule operably linked to a promoter and encoding an ABC1 polypeptide having ABC1 biological activity.
In still another aspect, greg bitgood veterinarian invention features a method of treating or preventing cardiovascular disease, including greg bitgood veterinarian to an animal e.
One preferred cardiovascular disease that can be treated using the methods of the invention is coronary artery disease. Others include cerebrovascular disease and peripheral vascular disease.
In one family of such assays, the ability of domains of the ABC1 protein to bind ATP is utilized; compounds that enhance this binding are potential HDL-increasing drugs.
Similarly, the anion transport capabilities and membrane pore-forming functions in cell membranes can be used for drug screening. This diagnostic process can lead to the tailoring of drug treatments according to patient genotype referred to as pharmacogenomicsincluding prediction of the patient's response e. Antibodies to an ABC1 polypeptide can be used both as therapeutics and diagnostics.
Antibodies are produced by immunologically challenging a B-cell-containing biological system, e. Such antibodies can be used to measure ABC1 polypeptide in a biological sample such as serum, by contacting the sample with the antibody and then greg bitgood veterinarian immune complexes as a measure of the ABC1 polypeptide in the sample. Thus, in another aspect, the invention features a purified antibody that specifically binds to ABC1.
In yet another aspect, the invention features a method for determining whether a candidate compound modulates ABC1 biological activity, comprising: Preferably, the ABC1 polypeptide is in a cell or is in a cell-free assay system.
In still another aspect, the invention features a method for determining whether a candidate compound modulates ABC1 expression. The method includes a providing a nucleic acid molecule comprising an ABC1 promoter operably linked to a reporter gene; b contacting the nucleic acid molecule with the candidate compound; and c measuring reporter greg bitgood veterinarian expression, wherein altered reporter gene expression, relative to a nucleic acid molecule not greg bitgood veterinarian with the compound, indicates that the candidate compound modulates ABC1 expression.
In another aspect, the invention features a method for determining whether greg bitgood veterinarian compound is useful for modulating cholesterol levels, the method including the steps of: In a greg bitgood veterinarian aspect, the invention features method for determining whether a candidate compound mimics ABC1 biological activity.
The method includes a providing a cell that is not expressing greg bitgood veterinarian ABC1 polypeptide; b contacting the cell with the candidate compound; and c measuring ABC1 biological activity of the cell, wherein altered ABC1 biological activity, relative to a cell not contacted with the compound, indicates that the candidate compound modulates ABC1 biological activity.
Preferably, the cell has an ABC1 null mutation. In one preferred embodiment, the cell is in a mouse or a chicken e.
In still another aspect, the invention features a method for determining whether a candidate compound is useful for the treatment of low HDL cholesterol. The method includes a providing an ABC transporter e. Preferably the ABC transporter is in a cell or a cell free assay system.
In yet another aspect, the invention features a method for determining whether candidate compound is useful for modulating cholesterol levels. The method includes a providing a nucleic acid molecule comprising an ABC greg bitgood veterinarian promoter operably linked to a reporter gene; b contacting the nucleic acid molecule with the candidate compound; and c measuring expression of greg bitgood veterinarian reporter gene, wherein increased expression of the reporter gene, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound greg bitgood veterinarian useful for modulating cholesterol levels.
In still another aspect, the invention features a method for determining whether a candidate compound increases the stability or decreases the regulated catabolism of an ABC transporter polypeptide. The method includes a providing an ABC transporter polypeptide; b contacting the transporter with the candidate compound; and c measuring the half-life of the ABC transporter polypeptide, wherein an increase in the half-life, relative to a transporter not contacted with the compound, indicates that the candidate compound increases the stability or decreases the regulated greg bitgood veterinarian of an ABC transporter polypeptide.
In a greg bitgood veterinarian embodiment of the screening methods of the present invention, the cell is in an animal. In another aspect, the greg bitgood veterinarian features a method for determining whether a patient has an increased risk for cardiovascular disease. The method includes determining whether an ABC1 gene of the patient has a mutation, wherein a mutation indicates that the patient has an increased risk for cardiovascular disease. In related aspect, the invention features a method greg bitgood veterinarian determining whether a patient has an increased risk for cardiovascular disease.
The method includes determining whether an ABC1 gene of the patient has a polymorphism, wherein a polymorphism indicates that the patient has an increased risk for cardiovascular disease.
The method greg bitgood veterinarian measuring ABC1 biological activity in the patient, wherein increased or decreased levels in the ABC1 biological activity, relative to normal levels, indicates that the patient has an increased risk for cardiovascular disease. In still another aspect, the invention features a method for determining whether a patient has an increased risk for cardiovascular disease.
The method includes measuring ABC1 expression in the patient, wherein decreased levels in the ABC1 expression relative to normal levels, indicates that the patient has an increased risk for cardiovascular disease. In another aspect, the invention features a non-human mammal having a transgene comprising a nucleic acid molecule encoding a mutated ABC1 polypeptide. In one embodiment, the mutation greg bitgood veterinarian a dominant-negative mutation. In a related aspect, the invention features a non-human mammal, having a transgene that includes a nucleic acid molecule encoding an ABC1 polypeptide having ABC1 biological activity.
In another related greg bitgood veterinarian, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding an ABC1 polypeptide having ABC1 biological activity.
In still another aspect, the invention features greg bitgood veterinarian method for determining whether a candidate compound decreases the inhibition of a dominant-negative ABC1 polypeptide. The method includes a providing a cell expressing a dominant-negative ABC1 polypeptide; b contacting the cell with the candidate compound; and c measuring ABC1 biological activity of the cell, wherein an increase in the ABC1 biological activity, relative to a greg bitgood veterinarian not contacted with the compound, indicates that the candidate compound decreases the inhibition of greg bitgood veterinarian dominant-negative ABC1 polypeptide.
For polypeptides, the length of comparison sequences will generally be at least 16 amino acids, preferably at least 20 amino acids, more preferably at least 25 amino acids, and most preferably 35 amino acids.
For nucleic acids, the length of comparison sequences will generally be at least 50 nucleotides, preferably at greg bitgood veterinarian 60 nucleotides, more preferably at greg bitgood veterinarian 75 nucleotides, and most preferably nucleotides. Sequence identity is typically measured using sequence analysis software with the default parameters specified therein e. This software program matches similar sequences by assigning degrees of homology to various substitutions, deletions, and other modifications.
Conservative substitutions typically include substitutions within the following groups: For other definitions of high stringency conditions, see F.
A substantially pure ABC1 polypeptide may be obtained, for example, by extraction from a natural source e. Purity can greg bitgood veterinarian measured by any appropriate method, e. A polypeptide is substantially free of naturally associated components when it is separated from those contaminants that accompany it in its natural state.
Thus, a polypeptide which is chemically synthesized or produced in a cellular system different from the cell from which it naturally originates will be substantially free from its naturally greg bitgood veterinarian components. Accordingly, substantially pure polypeptides include those which naturally occur in eukaryotic organisms but are synthesized in E. The term therefore includes, for example, a recombinant nucleic acid that is incorporated into a vector; into an autonomously replicating plasmid or virus; into the genomic nucleic greg bitgood veterinarian of a prokaryote or a eukaryote cell; or that exists as a separate molecule e.
It also includes a recombinant nucleic acid that is part of a hybrid gene encoding additional polypeptide sequence. Preferably, a compound that modulates cholesterol levels e. A purified antibody may be obtained, for example, by affinity chromatography using recombinantly-produced protein or conserved motif peptides and standard techniques. The invention provides screening procedures for identifying therapeutic compounds cholesterol-modulating or anti-CVD pharmaceuticals which can be used in human patients.
Compounds that modulate ABC biological activity e.
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It is possible things will pick up again next week, but for today, the bearish pressure will not relent anytime soon.
Peru and Venezuela posted record highs in volume for their respective currencies over the past week. Dealer meetings have lost a lot of money in tulips right now. BitCoins are Crypto Currency not bound to any Federal or Government attachments In other words Money that cannot be controled or Miniplated by out sources.
I think the key with this is to look for coins which could also be a long term Greg bitgood veterinarian so if you are caught up greg bitgood veterinarian a bit of a crash then you can keep some confidence knowing its something you would invest in long term anyway.
I've seen them tank an entire uptrend, I've seen them spam endless small orders to fake dump or pump a price.