Alexander G. Marneros

Alexander G. Marneros, M.D., Ph.D.

Alexander G. Marneros, MD/PhD Assistant Professor, Department of Dermatology, Harvard Medical School Dermatology Attending, Massachusetts General Hospital

Overview

WELCOME TO THE MARNEROS LAB

LABORATORY FOR ANGIOGENESIS,
WOUND HEALING AND INFLAMMATION

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.

 

Cell Reports

 

 

NEWS FROM OUR LAB:

 

 

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

MARNEROS LAB 

CUTANEOUS BIOLOGY CENTER

MASSACHUSETTS GENERAL HOSPITAL

CNY 149, 13TH ST. CHARLESTOWN, MA

                 CONTACT:

                ALEXANDER G. MARNEROS, M.D., PH.D
                 ASSISTANT PROFESSOR OF DERMATOLOGY
                 HARVARD MEDICAL SCHOOL
                 MASSACHUSETTS GENERAL HOSPITAL

         amarneros@mgh.harvard.edu


RESEARCH SUMMARY

 

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.

 

 3. REGULATION OF SKIN FORMATION DURING DEVELOPMENT: CAUSES OF CONGENTIAL WOUNDS

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.

 

Group Members

CURRENT LAB MEMBERS

Lizhi (Justin) He, PhD: Postdoctoral research fellow

Mariya Marioutina, B.Sc.: research technician

Jaclyn Andricovich, B.Sc.: research technician

Research Projects

Research Positions

 

A position for a highly dedicated and qualified postdoctoral research fellow is currently available.

 

 Please contact Alexander Marneros at 

amarneros@mgh.harvard.edu 

Publications

Selected Publications

 For the full publication list, search Pubmed for Marneros AG[au]

Strittmatter K, Pomeroy H,Marneros AG.Targeting PDGFRβ+ scaffold formation inhibits choroidal neovascularization. Am J Pathol, 2016, in press.
 
Marneros AG. Increased VEGF-A promotes multiple distinct aging diseases of the eye through shared pathomechanisms. EMBO Mol Med, 2016, 8(3): 208-231. PMID: 26912740.
 
Marneros, AG.Genetics of Aplasia Cutis Reveal Novel Regulators of Skin Morphogenesis. J Invest Dermatol, 2015, 135(3):666-672. PMID: 25355129

Ablonczy Z, Dahrouj M, Marneros AG.Progressive dysfunction of the retinal pigment epithelium and retina due to increased VEGF-A levels. FASEB J., 2014, May;28(5):2369-79. doi: 10.1096/fj.13-248021.

He L and Marneros AG.Doxycycline inhibits polarization of macrophages to the proangiogenic M2-type and subsequent neovascularization. J Biol Chem., 2014,JMar 21;289(12):8019-28. doi: 10.1074/jbc.M113.535765.

He L, Marioutina M, Dunaieff J, Marneros AG.Age- and gene dosage-dependent Cre-mediated abnormalities in the retinal pigment epithelium. Am J Pathol., 2014,iJun;184(6):1660-7. doi: 10.1016/j.ajpath.2014.02.007.

Marneros AG. NLRP3 Inflammasome Blockade Inhibits VEGF-A-Induced Age-Related Macular Degeneration. Cell Reports, 2013, 4(5): 945-958. Cover article.

He L and Marneros AG.  Macrophages are essential for the early wound healing response and the formation of a fibrovascular scar.  Am J.Pathol. 2013 182(6):2407-17 Cover article.

Marneros AG.BMS1 is mutated in Aplasia Cutis Congenita. Plos Genetics 2013, 9(6):e1003573.

Marneros AG*, Beck AE*, Turner EH, McMillin MJ, Edwards MJ, Field M, de Macena Sobreira NL, Perez AB, Fortes JA, Lampe AK, Giovannucci Uzielli ML, Gordon CT, Plessis G, Le Merrer M, Amiel J, Reichenberger E, Shively KM, Cerrato F, Labow BI, Tabor HK, Smith JD, Shendure J, Nickerson DA, Bamshad MJ; University of Washington Center for Mendelian Genomics. Mutations in KCTD1 cause scalp-ear-nipple syndrome. Am J Hum Genet. 2013 Apr 4;92  (4):621-6.

Makinodan E, Marneros AG.Protein kinase A activation inhibits oncogenic Sonic hedgehog signalling and suppresses basal cell carcinoma of the skin. Exp Dermatol. 2012;21(11):847-52.

Marneros, AG,Blanco F, Husain S, Silvers DN, Grossman ME. Classification of cutaneous intravascular breast cancer metastases based on immunolabeling of blood and lymph vessels. J Am Acad Derm, 2009;60(4):633-8.

Marneros AG, Grossman ME, Silvers DN, Husain S, Nuovo GJ, MacGregor-Cortelli B, Neylon E, Patterson M, O'Connor OA, Zain JM. Pralatrexate-induced tumor cell apoptosis in the epidermis of a patient with HTLV-1 adult T-cell lymphoma/leukemia causing skin erosions. Blood,2009;113(25):6338-41.

Marneros AG,She H, Zambarakji H, Hashimoto H, Connolly E, Kim I, Gragoudas E, Miller JW, Olsen BR. Endogenous endostatin inhibits choroidal neovascularization. FASEB J, 2007, 21(14):3809-3818.

Marneros AG, Fan J, Yokoyama Y, Gerber HP, Ferrara N, Crouch, RK, Olsen BR. VEGF expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol, 2005;167: 1349-1357.

Marneros AG,Keene DR, Hansen U, Fukai N, Moulton K, Goletz PL, Moiseyev G, Pawlyk BS, Halfter W, Dong S, Shibata M, Li T, Crouch RK, Bruckner P, Olsen BR. Collagen XVIII and endostatin are essential for vision and retinal pigment epithelial function. EMBO J., 2004;23(1):89-99.

 

 

 

Contact

Contact Us

Alexander G. Marneros, M.D., Ph.D.

Cutaneous Biology Research Center

Building 149, 13th Street Room 3.216Massachusetts General Hospital Charlestown, MA 02129
  • Near Public Transit
  • Accessible
  • Phone: 617-643-7170
  • Fax: 617-726-2120
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