Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a very common lethal monogenetic disease with significant morbidities and a high likelihood of progression to renal failure for which there is no proven disease-specific therapy currently available for clinical use. Human ADPKD cystic epithelia have proliferative abnormalities mediated by EGFR over-expression and mispolarization leading autocrine response to EGF family ligands. We now show that apical localization of EGFR complexes in normal fetal and ADPKD epithelia is associated with heterodimerization of EGFR(HER-1) with HER-2(neu/ErbB2), while basal membrane localization in normal adult renal epithelia is associated with EGFR(HER-1) homodimers. Since ADPKD epithelial cells have reduced migratory function, this was used as a bioassay to evaluate the ability of compounds to rescue the aberrant human ADPKD phenotype. General tyrosine kinase inhibition by herbimycin and specific inhibition of HER-2(neu/ErbB2) by AG825 or pretreatment with ErbB2 siRNA reversed the migration defect of ADPKD epithelia. Selective inhibition of EGFR(HER-1) showed partial rescue. Increased ADPKD cell migration after inhibition of p38MAP kinase but not of PI3-kinase implicated p38MAPK downstream of HER-2(neu/ErbB2) stimulation. Daily administration of AG825 to PKD1 null heterozygous mice significantly inhibited the development of renal cysts. These studies implicate HER2(neu/ErbB2) as an effector of apical EGFR complex mispolarization and that its inhibition should be considered a candidate for clinical therapy of ADPKD.
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PMID:Inhibition of HER-2(neu/ErbB2) restores normal function and structure to polycystic kidney disease (PKD) epithelia. 1679 38

Biologics are substances made from a living organism or its products. These include genes, proteins (eg, antibodies, receptors, enzymes, inhibitors), recombinant proteins, and fusion proteins. Biologics often are produced using recombinant DNA technology. For example, monoclonal antibodies are produced by inserting human genes into immortalized cell cultures, which then produce the gene product (ie, an antibody) in large quantity. Another approach is to fuse genetic material from nonhuman sources (eg, mice) with human genetic material. The fused gene is inserted into a tissue culture that produces the gene product (ie, a chimeric monoclonal antibody). Biologics are used to manage many conditions, including malignant and nonmalignant conditions. They are widely used in the treatment of human epidermal growth factor receptor 2 (ERBB2 [formerly HER2 or HER2/neu])-positive breast cancer. They also are used in the treatment of leukemias, lymphomas, and colorectal and lung cancer. Biologics improve outcomes in autoimmune disorders, such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, inflammatory bowel disease, and multiple sclerosis. Other uses include erythropoietin for renal failure-associated anemia and the new proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for treatment of patients with persistently elevated low-density lipoprotein levels despite statin treatment who are at high risk of cardiovascular events.
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PMID:Immunology Update: Biologics. 2786 38