Marneros Lab

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Overview

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

1. April 2022: Our paper that defines the roles of AP-2a and AP-2b transcription factors for distal nephron development and function has been accepted by Nature Communications.
2. November 2021: Our paper that defines key pathways regulating macrophage polarization states and that identified chemical inhibitors of IL-4-induced macrophage polarization has been published in, Cell Reports.   
    Mass General Press Release
3. January 2021: Our paper “Magnesium and calcium homeostasis depends on KCTD1 function in the distal nephron” has been published in Cell Reports.
   Mass General Press Release
4. November 2020: Our  paper on “Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization” has been accepted by eLife.     
   Mass General Press Release

5. June 2020: Identification of a critical role of AP-2b and KCTD1 for kidney development and renal fibrosis 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

   Mass General press release

6. Our Laboratory receives for second time competitive Age-related Macular Degeneration Research Award from the BrightFocus foundation.
7. Our laboratory receives two new NIH R01 grants to study novel mechanisms in kidney development and renal fibrosis. 

Research Projects

Research Program I: From wound healing to the identification of novel regulators of epithelial differentiation and fibrosis.

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 ribosome biogenesis defect and consequently a ribosomal stress response with p21 activation (PLoS Genetics, 2013). We also discovered causative gene mutations in KCTD1 in patients with Scalp-Ear-Nipple (SEN) syndrome who have aplasia cutis and additional abnormalities (Am J Hum Genet, 2013). We generated mice that lack KCTD1 and found that KCTD1 is a critical regulator of distal nephron differentiation: KCTD1 deficiency leads to a terminal differentiation defect in the distal nephron that causes a salt-losing tubulopathy and progressive renal fibrosis. Based on the findings in Kctd1 mutant mice, we reassessed SEN syndrome patients with KCTD1 mutations and found that they also develop progressive renal fibrosis and chronic kidney disease, expanding the clinical spectrum of the abnormalities that are part of this syndrome. Our detailed mouse genetics approaches showed that an AP-2b/KCTD1 axis controls distal nephron development and is also 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). Moreover, we found that KCTD1 is a critical regulator of magnesium and calcium transport processes in the distal nephron of the adult kidney (Cell Reports, 2021). These findings represent a major contribution to our understanding of the mechanisms that orchestrate distal nephron differentiation and have important translational relevance for SEN syndrome patients. We also found that the two closely related transcription factors AP-2a and AP-2b have distinct spatiotemporal roles in separate segments of the distal nephron, where they regulate the function and development of these segments (Nature Communications, 2022).

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Research Program II: From wound healing to macrophage polarization mechanisms and angiogenesis.

Aberrant angiogenesis exacerbates wound healing disorders, neovascular age-related macular degeneration (AMD), or tumor growth. We found in animal models of wound healing and neovascular AMD that polarization of macrophages to a proangiogenic subtype strongly promotes inflammatory angiogenesis, which can be blocked by ablation of these macrophages (Cell Reports, 2013; Am J Pathol, 2013; J Biol Chem, 2014). Identifying drugs that prevent this polarization process represents an important unmet clinical need. Global quantitative time-course proteomics, phosphoproteomics, and transcriptomics allowed us now to identify specific signaling nodes that are required for macrophage polarization processes. Drug screens identified drugs that selectively inhibited IL-4-induced proangiogenic macrophage polarization by blocking some of these signaling nodes. For example, we found that a MEK/PPARg/retinoic acid signaling axis is required for IL-4-induced macrophage polarization. We validated the clinical significance of these findings in mouse models of wound healing and neovascular AMD (Cell Reports, 2021). Our recent results offer exciting novel therapeutic opportunities to improve various diseases that are promoted by these polarized proangiogenic macrophages

 Research Program III: From wound healing to inflammasomes and neovascular AMD.

We investigate pathomechanisms that drive neovascular AMD, as this disease is promoted by inflammation that resembles a prolonged wound healing reaction. Progress in this field has been limited by a lack of a mouse model that forms spontaneous choroidal neovascularization (CNV). We identified a genetic mouse model for neovascular AMD that develops spontaneous CNV and AMD pathologies similarly as observed in the human disease, Vegfa^hyper mice. CNV forms in these mice as a consequence of chronically increased VEGF-A in the retinal pigment epithelium (RPE) (Cell Reports, 2013, FASEB J, 2014). This AMD mouse model confirmed the critical role of pro-angiogenic 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 inflammasomes potently inhibits CNV (EMBO Mol Med, 2016). Our recent new data answer key unresolved questions in the AMD field and show that not only NLRP3-dependent but also NLRP3-independent inflammasome activation in macrophages and microglia, but not in RPE cells, promotes CNV (eLife, 2020). These findings have important clinical relevance and suggest that inflammasome inhibitors can improve current neovascular AMD therapies.

Research Positions

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: amarneros@mgh.harvard.edu

Lab Members

CURRENT LAB MEMBERS

Qianyun Zhang, PhD
Lizhi He, PhD
Jakob Malsy, MD
Joseph Lamontagne
Alia Zeid
Sheryl Zhang
Alicia Rocha

Publications

Full publication list for Marneros AG[au]