Method For Evaluating Atherosclerotic Lesion, And Kit

Abstract

The present invention provides a method and a means for evaluating atherosclerotic lesions by identifying a protein (marker protein) group, the expression level of which varies according to the progression of the atherosclerotic lesion, and using the proteins. Specifically, the present invention relates to a method for evaluating atherosclerotic lesions, comprising the steps of detecting a marker protein exhibiting an expression pattern (expression variation) characteristic at a specific disease stage of atherosclerotic lesions in a subject, and evaluating the atherosclerotic lesions in the subject based on the detection result.

1 .- 23 . (canceled) 
     
     
         24 . A kit for evaluating an atherosclerotic lesion at the initial or the intermediate stage, comprising at least one type of substance specifically binding to plastin-2. 
     
     
         25 . A kit for evaluating the stage of an atherosclerotic lesion, comprising
 at least one type of substance specifically binding to plastin-2, and   at least one type of substance specifically binding to at least one type of protein selected from at least group (a), (b), or (d) from among proteins in the following groups (a) to (d):   (a) thrombospondin-4, fibromodulin, fibronectin, and cartilage oligomeric matrix protein;   (b) tenascin, CD5 antigen-like protein, properdin, Cb4-binding protein, fibrinogen beta chain, and fibrinogen gamma chain;   (c) vitronectin, matrix metalloproteinase-2, and thrombospondin-1;   (d) membrane-bound form immunoglobulin mu chain C region, receptor-type tyrosine protein phosphatase C, immunoglobulin gamma-2B chain-C region, immunoglobulin J chain, immunoglobulin kappa chain C region, vascular cell adhesion protein 1, alpha-2-macroglobulin, ADAMTS-like protein 4, cathepsin B, carboxy peptidase-B2, complement factor-H, clusterin, collagen alpha-1 (XIV) chain, epidermal fatty acid-binding protein, mannose-binding lectin-associated serine protease-2, prothrombin, complement factor B, inter-alpha-trypsin inhibitor-heavy chain-H1, myosin-9, vitamin K-dependent factor S, metalloproteinase inhibitor 3, and tropomyosin alpha 4.   
     
     
         26 . The kit according to  claim 25 , wherein the protein selected from group (a) is thrombospondin-4. 
     
     
         27 . The kit according to  claim 25 , wherein the protein selected from group (b) is a protein selected from properdin and CD5 antigen-like protein. 
     
     
         28 . The kit according to  claim 25 , wherein the protein selected from group (d) is a protein selected from epidermal fatty acid-binding protein, myosin-9 and ADAMTS-like protein 4. 
     
     
         29 . The kit according to  claim 25 , the evaluation of the stage of an atherosclerotic lesion is selected from the group consisting of the determination of the presence of an atherosclerotic lesion at a certain stage in a subject, the determination of the stage of an atherosclerotic lesion in a subject, the determination of the location of an atherosclerotic lesion at a certain stage in a subject, the evaluation of the therapeutic effect on arteriosclerosis at a certain stage existing in a subject, and the prediction of prognosis of arteriosclerosis existing in a subject. 
     
     
         30 . The kit according to  claim 24 , wherein a substance specifically binding to a protein is selected from the group consisting of an antibody, an antibody-like molecule, a nucleic acid aptamer, a ligand, and a substrate. 
     
     
         31 . The kit according to  claim 24 , wherein the substance specifically binding to a protein is bound to a contrast medium. 
     
     
         32 . The kit according to  claim 31 , wherein the contrast medium is selected from the group consisting of a fluorescent substance, a luminescent substance, a radioactive substance, a liposome, a micelle, a cell, a virus particle, a virus, a microparticle, a nanoparticle, a microdevice with a space, an emulsion, a lipid disc, a polymer, a gadolinium-conjugated molecule, a superparamagnetic iron oxide particle, a perfluorocarbon nanoparticle, and an ultrafine bubble. 
     
     
         33 . The kit according to  claim 31 , wherein the atherosclerotic lesion is visualized by a means selected from the group consisting of positron emission tomography (PET), single photon emission computed tomography (SPECT), γ scintigraphy, autoradiography, fluorescent imaging, magnetic resonance imaging (MRI), ultrasonication, and computed tomography (CT). 
     
     
         34 . An apparatus for evaluating an atherosclerotic lesion at the initial or the intermediate stage, comprising:
 (i) a means of detecting plastin-2 in a subject:   (ii) a means of evaluating the atherosclerotic lesion at the initial or the intermediate stage in the subject based on the detection results obtained by means (i).   
     
     
         35 . An apparatus for evaluating the stage of an atherosclerotic lesion, comprising:
 (i) a means of detecting plastin-2 in a subject and a means of detecting at least one type of protein selected from at least group (a), (b), or (d) from among proteins shown in the following groups (a) to (d) in a subject:   (a) thrombospondin-4, fibromodulin, fibronectin, and cartilage oligomeric matrix protein;   (b) tenascin, CD5 antigen-like protein, properdin, Cb4-binding protein, fibrinogen beta chain, and fibrinogen gamma chain;   (c) vitronectin, matrix metalloproteinase-2, and thrombospondin-1; and   (d) membrane-bound form immunoglobulin mu chain C region, receptor-type tyrosine protein phosphatase C, immunoglobulin gamma-2B chain-C region, immunoglobulin J chain, immunoglobulin kappa chain C region, vascular cell adhesion protein 1, alpha-2-macroglobulin, ADAMTS-like protein 4, cathepsin B, carboxy peptidase-B2, complement factor-H, clusterin, collagen alpha-1 (XIV) chain, epidermal fatty acid-binding protein, mannose-binding lectin-associated serine protease-2, prothrombin, complement factor B, inter-alpha-trypsin inhibitor-heavy chain-H1, myosin-9, vitamin K-dependent factor S, metalloproteinase inhibitor 3, and tropomyosin alpha 4; and   (ii) a means of evaluating the stage of the atherosclerotic lesion in the subject based on the detection results obtained by means (i).   
     
     
         36 . The apparatus according to  claim 34 , further comprising:
 (iii) a means of storing the standard levels of the above proteins; and   (iv) a means of comparing the protein detection results in the subject with the standard levels.   
     
     
         37 . An agent for visualizing an atherosclerotic lesion at the initial or the intermediate stage, comprising at least one type of substance specifically binding to plastin-2, and a contrast medium binding thereto. 
     
     
         38 . An agent for visualizing an atherosclerotic lesion at a certain stage, comprising
 at least one type of substance specifically binding to plastin-2 and a contrast medium binding thereto, and   at least one type of protein selected from at least group (a), (b), or (d) from among proteins in the following groups (a) to (d) and a contrast medium binding thereto:   (a) thrombospondin-4, fibromodulin, fibronectin, and cartilage oligomeric matrix protein;   (b) tenascin, CD5 antigen-like protein, properdin, Cb4-binding protein, fibrinogen beta chain, and fibrinogen gamma chain;   (c) vitronectin, matrix metalloproteinase-2, and thrombospondin-1; and   (d) membrane-bound form immunoglobulin mu chain C region, receptor-type tyrosine protein phosphatase C, immunoglobulin gamma-2B chain-C region, immunoglobulin J chain, immunoglobulin kappa chain C region, vascular cell adhesion protein 1, alpha-2-macroglobulin, ADAMTS-like protein 4, cathepsin B, carboxy peptidase-B2, complement factor-H, clusterin, collagen alpha-1 (XIV) chain, epidermal fatty acid-binding protein, mannose-binding lectin-associated serine protease-2, prothrombin, complement factor B, inter-alpha-trypsin inhibitor-heavy chain-H1, myosin-9, vitamin K-dependent factor S, metalloproteinase inhibitor 3, and tropomyosin alpha 4.   
     
     
         39 . A targeting agent for directing a compound or a molecule to an atherosclerotic lesion at the initial or the intermediate stage, comprising a substance specifically binding to plastin-2 and the compound or the molecule binding thereto. 
     
     
         40 . A targeting agent for directing a compound or a molecule to an atherosclerotic lesion at a certain stage, comprising
 a substance specifically binding to plastin-2 and the compound or the molecule binding thereto, and   a substance specifically binding to at least one type of protein selected from at least group (a),   (b), or (d) from among the following groups (a) to (d), and the compound or the molecule binding thereto:   (a) thrombospondin-4, fibromodulin, fibronectin, and cartilage oligomeric matrix protein;   (b) tenascin, CD5 antigen-like protein, properdin, Cb4-binding protein, fibrinogen beta chain, and fibrinogen gamma chain;   (c) vitronectin, matrix metalloproteinase-2, and thrombospondin-1; and   (d) membrane-bound form immunoglobulin mu chain C region, receptor-type tyrosine protein phosphatase C, immunoglobulin gamma-2B chain-C region, immunoglobulin J chain, immunoglobulin kappa chain C region, vascular cell adhesion protein 1, alpha-2-macroglobulin, ADAMTS-like protein 4, cathepsin B, carboxy peptidase-B2, complement factor-H, clusterin, collagen alpha-1 (XIV) chain, epidermal fatty acid-binding protein, mannose-binding lectin-associated serine protease-2, prothrombin, complement factor B, inter-alpha-trypsin inhibitor-heavy chain-H1, myosin-9, vitamin K-dependent factor S, metalloproteinase inhibitor 3, and tropomyosin alpha 4.   
     
     
         41 . The targeting agent according to  claim 39 , wherein the compound or the molecule is a thrombolytic agent. 
     
     
         42 . A method for evaluating the effectiveness of a therapeutic agent or a therapeutic method for an atherosclerotic lesion at the initial or the intermediate stage, comprising the steps of:
 (i) detecting plastin-2 in an animal with an atherosclerotic lesion at the initial or the intermediate stage treated by a test therapeutic agent or a test therapeutic method:   (ii) evaluating the effectiveness of the test therapeutic agent or the test therapeutic method on the atherosclerotic lesion at the initial or the intermediate stage based on the results of (i).   
     
     
         43 . A method for evaluating the effectiveness of a therapeutic agent or a therapeutic method for an atherosclerotic lesion at a certain stage, comprising the steps of:
 (i) detecting plastin-2 and at least one type of protein selected from at least group (a), (b), or (d) from among proteins shown in the following groups (a) to (d) in an animal with an atherosclerotic lesion treated by a test therapeutic agent or a test therapeutic method:   (a) thrombospondin-4, fibromodulin, fibronectin, and cartilage oligomeric matrix protein;   (b) tenascin, CD5 antigen-like protein, properdin, Cb4-binding protein, fibrinogen beta chain, and fibrinogen gamma chain;   (c) vitronectin, matrix metalloproteinase-2, and thrombospondin-1; and   (d) membrane-bound form immunoglobulin mu chain C region, receptor-type tyrosine protein phosphatase C, immunoglobulin gamma-2B chain-C region, immunoglobulin J chain, immunoglobulin kappa chain C region, vascular cell adhesion protein 1, alpha-2-macroglobulin, ADAMTS-like protein 4, cathepsin B, carboxy peptidase-B2, complement factor-H, clusterin, collagen alpha-1 (XIV) chain, epidermal fatty acid-binding protein, mannose-binding lectin-associated serine protease-2, prothrombin, complement factor B, inter-alpha-trypsin inhibitor-heavy chain-H1, myosin-9, vitamin K-dependent factor S, metalloproteinase inhibitor 3, and tropomyosin alpha 4; and   (ii) evaluating the effectiveness of the test therapeutic agent or the test therapeutic method on the atherosclerotic lesion at a certain stage based on the results of (i).   
     
     
         44 . The method according to  claim 42 , further comprising a step of detecting the protein in an animal with an atherosclerotic lesion before treatment using the test therapeutic agent or the test therapeutic method. 
     
     
         45 . The method according to  claim 42 , wherein an animal having an atherosclerotic lesion is an arterial disease animal model.