Cutaneous Biology Research Center
149 13th Street
Charlestown, MA 02129-2000
Alexander G. Marneros, MD, PhD
Physician Investigator, Cutaneous Biology Research Center, Massachusetts General Hospital
Associate Professor of Dermatology, Harvard Medical School
Explore This Lab
Our laboratory is interested in mechanisms that affect wound healing, epithelial biology, inflammation, angiogenesis and fibrosis. Our work has a particular focus on how these processes affect age-related diseases, such as age-related macular degeneration or chronic kidney disease.
News from Our Laboratory
- November 2020: Our new paper on “Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization” has now been accepted by eLife.
June 17, 2020: Identification of a critical role of AP-2b and KCTD1 for kidney development and renal fibrosis, now published in Developmental Cell.
We show that the transcription factor AP-2b induces differentiation of distal tubule precursors into early stage distal convoluted tubules (DCTs), whereas its downstream target KCTD1 is required for their terminal differentiation into mature DCTs. KCTD1 loss causes immature DCTs, leading to a salt-losing tubulopathy followed by renal fibrosis via b-catenin hyperactivation.
“AP-2b/KCTD1 Control Distal Nephron Differentiation and Protect against Renal Fibrosis”, Developmental Cell (2020), https://doi.org/10.1016/j.devcel.2020.05.026
- Our Laboratory receives for second time competitive Age-related Macular Degeneration Research Award from the BrightFocus foundation.
- Our laboratory receives two new NIH R01 grants to study novel mechanisms in kidney development and renal fibrosis.
Project #1: Identifying key pathways involved in skin formation by discovery of gene mutations causing congenital skin formation defects
We use human genetics to discover gene mutations that cause aplasia cutis, which manifests with congenital skin wounds due to a localized failure of skin formation. We identified the first causative gene for aplasia cutis as the ribosomal GTPase BMS1 that when mutated leads to a ribosomal stress response and p21 activation (PLoS Genetics, 2013). We also identified causative gene mutations in KCTD1 in patients with Scalp-Ear-Nipple (SEN) syndrome that manifests with aplasia cutis and additional ectodermal abnormalities (Am J Hum Genet, 2013). Functions for these genes in the skin were previously unknown. We generated mice that lack KCTD1 and uncovered that KCTD1 is not only important for skin formation but is particularly critical for kidney function. KCTD1 deficiency leads to a salt-losing tubulopathy and severe progressive renal fibrosis in these mice. Based on the findings in KCTD1 mutant mice we reassessed patients with KCTD1 mutations and found that SEN syndrome patients also develop progressive renal fibrosis and chronic kidney disease, expanding the clinical spectrum of the abnormalities that are part of this syndrome. Detailed mouse genetic approaches showed that an AP-2b/KCTD1 axis controls distal nephron development and is required for the maintenance of the terminal differentiation state of the distal nephron in the adult. Loss of terminal differentiation of the distal nephron owing to lack of AP-2b or KCTD1 leads to progressive renal fibrosis due to b-catenin hyperactivation and increased mTOR activity (Dev Cell, 2020). These findings not only provide the first detailed understanding of the mechanisms that orchestrate distal nephron differentiation but also have important translational relevance for SEN syndrome patients and for patients with renal fibrosis.
Project #2: Selective targeting of proangiogenic macrophages in wounds and in neovascular age-related macular degeneration (AMD)
Aberrant angiogenesis exacerbates wound healing disorders and other common diseases, such as neovascular AMD or tumor growth. We found in animal models of wound healing and neovascular AMD that proangiogenic M2-type macrophages strongly promote inflammatory angiogenesis, which can be blocked by ablation of these proangiogenic macrophages (Cell Reports, 2013; Am J Pathol, 2013; J Biol Chem, 2014). Using small molecule inhibitor screens we found that specific drugs can selectively inhibit proangiogenic M2-type macrophage polarization without affecting antiangiogenic M1-type macrophages. Combining these data with quantitative time-course proteomics, phosphoproteomics and transcriptomics allowed us to identify specific signaling nodes that are required for M2-type polarization and that can be selectively blocked by drugs that are currently in clinical use for other indications and that could, thus, be repurposed for the treatment of diseases promoted by M2-type macrophages. We found that a novel signaling axis is required for M2-type polarization and that its pharmacologic blockade can selectively prevent M2-type polarization. We validated the clinical significance of these findings in mouse models of wound healing and neovascular AMD, where the identified inhibitors prevented M2-type polarization and pathologic angiogenesis. Our results offer broad novel therapeutic opportunities to improve many diseases that are promoted by M2-type macrophages.
Project #3: Role of the inflammasome for inflammatory angiogenesis
A prototypical disease to study the effects of abnormal blood vessels for disruption of tissue function is neovascular AMD. However, progress has been hindered by a lack of a mouse model that forms spontaneous choroidal neovascularization (CNV). We identified the first genetic mouse model for neovascular AMD that develops spontaneous CNV and AMD pathologies as observed in the human disease, VEGF-Ahyper mice. CNV forms in these mice as a consequence of chronically increased VEGF-A expression in the retinal pigment epithelium (RPE) (Cell Reports, 2013, FASEB J, 2014). This AMD mouse model confirmed the critical role of proangiogenic macrophages for CNV formation. Moreover, we discovered that increased NLRP3 inflammasome activation promotes CNV via secretion of proangiogenic IL-1b, whereas genetic or pharmacologic targeting of the inflammasome potently inhibits CNV (EMBO Mol Med, 2016). Our new data resolve key unresolved questions in the AMD field and have important translational relevance, as they demonstrate that pharmacologic targeting of inflammasomes can inhibit neovascular AMD.
A Postdoctoral Research Fellow position is available for a highly qualified individual with expertise in biochemical assays and mouse in vivo work. Experience in computational biology is preferred. Interested candidates should send their information including CV and the name of 2-3 references to Dr. Alexander G. Marneros: email@example.com
CURRENT LAB MEMBERS
Lizhi He, PhD
Jakob Malsy, MD
Malsy J, Alvarado AC, Lamontagne JO, Strittmatter K, Marneros AG. Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization. eLife, 2020 (in press).
Marneros AG. AP-2b/KCTD1 Control Distal Nephron Differentiation and Protect against Renal Fibrosis, Developmental Cell. 2020, https://doi.org/10.1016/j.devcel.2020.05.026
Marneros AG. Effects of chronically increased VEGF-A on the aging heart. Am J Pathol. 2018 Mar;32(3):1550-1565. doi: 10.1096/fj.201700761RR.
Strittmatter K, Pomeroy H, Marneros AG. Targeting PDGFRβ+ scaffold formation inhibits choroidal neovascularization. Am J Pathol. 2016, 186(7):1890-9.
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, Marneros AG. Doxycycline inhibits polarization of macrophages to the proangiogenic M2-type and subsequent neovascularization. J Biol Chem. 2014, Mar 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, Jun;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, 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.