title: Pathway activation profiling reveals new insights into age-related macular degeneration and provides avenues for therapeutic interventions.
abstract: Age-related macular degeneration (AMD) is a major cause of blindness in older people and is caused by loss of the central region of the retinal pigment epithelium (RPE). Conventional methods of gene expression analysis have yielded important insights into AMD pathogenesis, but the precise molecular pathway alterations are still poorly understood. Therefore we developed a new software program, "AMD Medicine", and discovered differential pathway activation profiles in samples of human RPE/choroid from AMD patients and controls. We identified 29 pathways in RPE-choroid AMD phenotypes: 27 pathways were activated in AMD compared to controls, and 2 pathways were activated in controls compared to AMD. In AMD, we identified a graded activation of pathways related to wound response, complement cascade, and cell survival. Also, there was downregulation of two pathways responsible for apoptosis. Furthermore, significant activation of pro-mitotic pathways is consistent with dedifferentiation and cell proliferation events, which occur early in the pathogenesis of AMD. Significantly, we discovered new global pathway activation signatures of AMD involved in the cell-based inflammatory response: IL-2, STAT3, and ERK. The ultimate aim of our research is to achieve a better understanding of signaling pathways involved in AMD pathology, which will eventually lead to better treatments.
authors.affiliation: Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Makarev
authors.affiliation: Boston University, Boston, MA 02215, USA. Retrotope, Inc, Los Altos Hills, CA 94022, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Cantor
authors.affiliation: Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD 21218, USA. The Biogerontology Research Foundation, London, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Zhavoronkov
authors.affiliation: Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD 21218, USA. Pathway Pharmaceutivals, Ltd, Hong Kong.
authors.forename: Anton
authors.initials: A
authors.lastname: Buzdin
authors.affiliation: Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Aliper
authors.affiliation: Vision Genomics, LLC, Washington, DC 20010, USA. Epigenetics Laboratory, Dept. of Anatomy, Howard University, Washington, DC 20059, USA.
authors.forename: Anotonei Benjamin
authors.initials: AB
authors.lastname: Csoka
mesh_terms: D016022:Case-Control Studies; D019295:Computational Biology; D030541:Databases, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D055213:Retinal Pigment Epithelium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012985:Software Design
chemical_list: D005819:Genetic Markers