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Cutaneous Biology Research Center
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We are interested in the molecular and cellular mechanisms that drive pathological angiogenesis. Our work focuses on growth factors and inflammatory cells that regulate abnormal blood vessel formation in inflammation, wound healing, and age-related macular degeneration.
We recently identified a new mouse model of age-related macular degeneration and showed that increased VEGF-A is sufficient to cause both non-exudative and neovascular age-related macular degeneration. Targeting the NLRP3 inflammasome inhibits the progression of this blinding disease.
Cell Rep. 2013; 4(5)945-58. Cover article
CUTANEOUS BIOLOGY CENTER
MASSACHUSETTS GENERAL HOSPITAL
CNY 149, 13TH ST. CHARLESTOWN, MA
ALEXANDER G. MARNEROS, M.D., PH.D ASSISTANT PROFESSOR OF DERMATOLOGY HARVARD MEDICAL SCHOOL MASSACHUSETTS GENERAL HOSPITAL
Abnormal blood vessel growth is an important component in the pathogenesis of various common diseases. Pathological angiogenesis is stimulated by an inflammatory response that involves many different cell types, including proangiogenic macrophages. Our laboratory focuses on the factors and cell types that promote pathologic angiogenesis in development, in the adult and during aging.
Flat mount of a choroidal neovascular lesion in mice with increased VEGF-A levels. Macrophages (white) infiltrate sites of breakdown of the RPE barrier (red, beta-catenin), resulting in neovascularization into the subretinal space (Cell Rep. 2013; 4(5):945-58).
1. ABNORMAL ANGIOGENESIS DURING AGING: AGE-RELATED MACULAR DEGENERATION.
Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the elderly. Non-exudative ("dry") AMD manifests with degeneration of the retinal pigment epithelium (RPE) and sub-RPE deposit formation with progressive age. Neovascular ("wet") AMD manifests with pathologic neovascularization from the choroid into the retina. Often both forms co-occur, suggesting a common pathomechanism. We have recently shown in a new mouse model of AMD that increased VEGF-A is sufficient to cause both forms of AMD, providing evidence for a unifying pathomechanism in advanced AMD. In this model, proangiogenic macrophages stimulate retinal glia cells to promote choroidal neovascularization. Furthermore, we could show that the NLRP3 inflammasome promotes VEGF-A-induced AMD pathologies, and targeting inflammasome components inhibits these pathologies. Our work focuses on elucidating the mechanisms that regulate molecular pathways and cellular interactions during AMD pathogenesis, with the aim of identifying novel therapeutic approaches for patients with AMD.
Laser-induced choroidal neovascularization is promoted by activated macrophages. Targeted ablation of macrophages inhibits neovascularization (CD31+ vessels in green) in response to laser injury (Am J Pathol. 2013; 182(6):2407-17; Cell Rep. 2013; 4(5):945-58).
2. ROLE OF MACROPHAGES IN ANGIOGENESIS AND THE WOUND HEALING RESPONSE
Multiple cell types interact in a highly coordinated fashion in response to injury to promote wound healing. Abnormalities in this complex process can result in exuberant wound angiogenesis or scarring.We use in vivo models of wound healing to determine the spatiotemporal contributions of various cell types in this process. In a laser-injury model of choroidal neovascularization, we could show that macrophages become alternatively activated (M2-type) and promote wound angiogenesis, in part by stimulating retinal glia cells to express proangiogenic growth factors. Specific ablation of macrophages inhibits the early wound healing response to injury and blocks wound angiogenesis. Our current research investigates which signaling pathways drive polarization of macrophages to the proangiogenic M2-type in vivo and how this polarization can be inhibited. Overall, we aim to define the contributions of individual inflammatory cell populations to wound healing and neovascularization.
Automomal dominant aplasia cutis congenita is caused by a mutation in the ribosomal biogenesis GTPase BMS1. The mutation results in a maturation defect of the small ribosomal subunit and a p21-mediated nucleolar stress response that leads to reduced cell proliferation. (PLos Genet. 2013; 9(6):e1003573.
Wound healing and wound angiogenesis occur in response to injury. However, congenital wounds are observed in various genetic syndromes as a manifestation of a skin morphogenesis defect during embryonic development. Identifying the genetic basis for these conditions and syndromes promises to identify novel genes and pathways that are critical for proper skin formation and whose impairment results in wounds. A prototypical congenital skin disease that manifests with a wound present at birth is aplasia cutis congenita (ACC). Using a combination of genome-wide linkage analysis and exome sequencing we recently identified the causative mutation for ACC. We found that the ribosomal GTPase BMS1 is mutated in ACC, which results in a maturation defect of the small ribosomal subunit and leads to a nucleolar stress response with a p21-mediated G1/S phase transition delay and a reduced cell proliferation rate. Global proteomic and transcriptional analyses revealed a central role of p21 activation for the ACC phenotype.
Our laboratory investigates how a mutation in a ubiquitous ribosomal protein leads to localized skin defects without affecting other organ systems. We seek to obtain a comprehensive understanding of the disease mechanisms of congenital wound healing disorders.
CURRENT LAB MEMBERS
Lizhi (Justin) He, PhD: Postdoctoral research fellow
Mariya Marioutina, B.Sc.: research technician
Jaclyn Andricovich, B.Sc.: research technician
A position for a highly dedicated and qualified postdoctoral research fellow is currently available.
Please contact Alexander Marneros at
For the full publication list, search Pubmed for Marneros AG[au]
Alexander G. Marneros, M.D., Ph.D.
Cutaneous Biology Research Center
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