Differential gene expression in physiological and pathological angiogenesis

Abstract

Methods of inhibiting pathological angiogenesis in a subject are disclosed. In particular examples, the method includes administering a therapeutically effective amount of a composition to a subject wherein the composition includes a specific binding agent that preferentially binds to one or more pathological angiogenesis marker proteins including Vscp, CD276, ETSvg4 (Pea3), CD137 (4-1BB), MiRP2, Ubiquitin D (Fat10), Doppel (prion-PLP), Apelin, Plgf, Ptpm (IA-2), CD109, Ankylosis, and collagen VIIIα1. In additional examples, methods to deliver a therapeutic agent to a brain or liver endothelial cell are also disclosed.

We claim: 
     
         1 . A method of determining pathological angiogenesis, comprising:
 contacting a sample obtained from a subject with a first probe or primer set capable of detecting at least a first expression product selected from the group consisting of Vscp, ETSvg4 (Pea3), CD137 (4-1BB), MiRP2, Ubiquitin D (Fat10), Doppel (prion-PLP), Apelin, Plgf, CD109, Ankylosis, and collagen VIII and a second probe or primer set capable of detecting at least a second expression product selected from the group consisting of Vscp, ETSvg4 (Pea3), CD137 (4-1BB), MiRP2, Ubiquitin D (Fat10), Doppel (prion-PLP), Apelin, Plgf, CD109, Ankylosis, and collagen VIII, in a sample obtained from the subject;   detecting the at least first expression product and the at least second expression product in the sample obtained from the subject by performing an assay that detects both the at least first and second expression products; and   determining the presence of pathological angiogenesis in the subject by comparing expression level of the first expression product and the second expression product in the sample obtained from the subject with the expression level of the first expression product and second expression product in a control sample wherein detection of an increase in expression of the at least first and second expression products as compared to expression of the at least first and second expression products in a control sample indicates pathological angiogenesis.   
     
     
         2 . The method of  claim 1 , wherein detection of an increase in expression of the at least first and second expression products indicates the presence of a tumor. 
     
     
         3 . The method of  claim 2 , wherein the expression products are RNA or protein. 
     
     
         4 . The method of  claim 2 , wherein the tumor is a cancer of the colon, liver, lung, or breast. 
     
     
         5 . The method of  claim 1 , wherein the detecting the at least first and second expression products is performed using serial analysis gene expression (SAGE), polymerase chain reaction, Western blot, or immunoassay. 
     
     
         6 . The method of  claim 1 , wherein the sample is serum sample. 
     
     
         7 . The method of  claim 1 , wherein the method is used to detect the efficacy of an anti-angiogenic agent for treating pathological angiogenesis. 
     
     
         8 . A method of delivering a therapeutic agent to brain endothelial cells or liver endothelial cells, comprising:
 administering a therapeutically effective amount of a composition, wherein the composition comprises a therapeutic agent and a binding agent that preferentially binds to one or more brain endothelial marker proteins comprising Glucose transporter GLUT-1, Organic anion transporter 2, Pleiotrophin, ATPase class V, type 10A, Peptidoglycan recognition protein 1, Organic anion transporter 14, Forkhead box Q1, Organic anion transporter 3, SN2 (Solute carrier family 38, member 5), Inter-alpha (globulin) inhibitor H5, Solute carrier 38 member 3, Zinc finger protein of the cerebellum 2, Testican-2, 3-HMG-CoA synthase 2, Progestin and adipoQ receptor family member V, APC down-regulated 1 Drapc1, GDPD phosphodiesterase family Accession No. NM — 001042671, putative transmembrane protein Accession No. NM — 029001, DES2 lipid desaturase/C4-hyroxylase, Kelch repeat and BTB (POZ) domain, Lipolysis stimulated receptor, Glutathione S-transferase alpha 4, TNF receptor superfamily member 19, T-box 1 or putative secreted protein Accession No. XM — 620023, thereby evoking a therapeutic response in the brain endothelial cells or the cells underlying the brain endothelial cells or   administering a therapeutically effective amount of a composition, wherein the composition comprises a therapeutic agent and a binding agent that specifically binds to one or more liver endothelial marker proteins comprising deoxyribonuclease 1-like 3, LZP oncoprotein induced transcript 3, putative transmembrane protein Accession No. NM — 023438, CD32 15, putative G-protein coupled receptor NM — 033616, C-type lectin-like receptor 2, C-type lectin domain family 4 member g 16, Plexin C1, Wnt9B, Accession No. AK144596, GATA-binding protein 4, MBL-associated serine protease-3, Renin binding protein, putative transmembrane protein Accession No. NM — 144830, or Retinoic acid receptor, beta, thereby evoking a therapeutic response in the liver endothelial cells.   
     
     
         9 . The method of  claim 8 , wherein the specific binding agent is an antibody to one or more of the brain endothelial markers, wherein the antibody is conjugated to the therapeutic agent and wherein the therapeutic agent comprises a cytotoxin, chemotherapeutic reagent, radionucleotide, or combination thereof. 
     
     
         10 . The method of  claim 9 , wherein the brain endothelial marker protein comprises GDPD phosphodiesterase family Accession No. NM — 001042671, Forkhead box Q1 (FOXQ1), putative transmembrane protein Accession No. NM — 029001, Kelch repeat and BTB (POZ) domain, Progestin and adipoQ receptor family member V, or putative secreted protein Accession No. XM — 620023. 
     
     
         11 . The method of  claim 9 , wherein the specific binding agent is an antibody, wherein the antibody is conjugated to the therapeutic agent, and wherein the therapeutic agent comprises a cytotoxin, chemotherapeutic reagent, radionucleotide, or combination thereof. 
     
     
         12 . The method of  claim 8 , wherein the liver endothelial marker protein comprises oncoprotein induced transcript 3, putative transmembrane protein Accession No. NM — 023438, putative G-protein coupled receptor NM — 033616, Plexin C1, MBL-associated serine protease-3, Accession No. AK144596, or putative transmembrane protein Accession No. NM — 144830. 
     
     
         13 . A method of inhibiting pathological angiogenesis in a subject, comprising:
 administering to the subject a therapeutically effective amount of a composition, wherein the composition comprises a specific binding agent that preferentially binds to one or more pathological angiogenesis marker proteins comprising Vscp, CD276, ETSvg4 (Pea3), CD137 (4-1BB), MiRP2, Ubiquitin D (Fat10), Doppel (prion-PLP), Apelin, Plgf, Ptprn (IA-2), CD109, Ankylosis, and collagen VIIIα1, thereby inhibiting pathological angiogenesis in the subject.   
     
     
         14 . The method of  claim 13 , wherein the one or more pathological angiogenesis marker proteins is Vscp, CD276, MiRP2, Ptprn (IA-2), or ankylosis. 
     
     
         15 . The method of  claim 13 , wherein the specific binding agent significantly reduces the biological activity of the one or more pathological angiogenesis marker proteins. 
     
     
         16 . The method of  claim 13 , wherein the specific binding agent further comprises a therapeutic molecule. 
     
     
         17 . The method of  claim 16 , wherein the specific binding agent is an antibody to one or more of the pathological angiogenesis marker proteins conjugated to the therapeutic molecule. 
     
     
         18 . The method of  claim 17 , wherein the therapeutic molecule is a cytotoxin, chemotherapeutic reagent, radionucleotide, or combination thereof. 
     
     
         19 . The method of  claim 13 , wherein inhibiting pathological angiogenesis treats a tumor, and the composition includes a specific binding agent that preferentially binds to one or more of: Vscp, CD276, ETSvg4 (Pea3), MiRP2, Ubiquitin D (Fat10), Doppel (prion-PLP), Apelin, Plgf, Ptprn (IA-2), CD109, Ankylosis, or collagen VIII. 
     
     
         20 . The method of  claim 19 , wherein the specific binding agent is an antibody to one or more of: Vscp, CD276, ETSvg4 (Pea3), MiRP2, Ubiquitin D (Fat10), Doppel (prion-PLP), Apelin, Plgf, Ptprn (IA-2), CD109, Ankylosis, or collagen VIII conjugated to a therapeutic molecule.