Hermann Haller, M.D.

Program in Cellular & Molecular Physiology: Membrane Biology

The main focus of our research group is to understand the pathophysiology of proteinuria, the mechanism whereby the capillary wall in the renal glomerulus is altered and albumin and other molecules cross the multi-layered membrane. Proteinuria is the hallmark of acute and chronic kidney damage and its understanding is not only of pathophysiologic interest, but may also lead to novel therapeutic strategies for renal disease.

Since several cellular systems are involved in the integrity oft he capillary wall we focus both on endothelial cells (Hermann Haller) and podocytes (Mario Schiffer). The main questions with regard to the endothelium are (1) the differentiation of these cells into specialized “fenestrated” cells, (2) the expression and function of its glycocalyx layer, and (3) the secretion of cytokines, which are important for the communication between endothelium and podocytes.

We developed a novel model system for proteinuria screening in developing zebrafish larvae using transgenic fish and fluorescent plasma protein to measure proteinuria in screening assays to analyze the molecular mechanisms of capillary permeability and to identify novel therapeutic targets to prevent proteinuria.

Zebrafish are an ideal model to test gene deletion by using morpholino or antisense strategies. Recent work with the zebrafish model has extended from the study of developmental biology to a wide array of experimental studies relevant to human disease. The zebrafish is an effective model-species to examine the direct effects of gene targeting in a vertebrate, particularly in the context of kidney development.

Zebrafish development occurs rapidly from the fertilized egg to free-swimming larvae in 2.5 days and the embryos have transparent internal organ development that can be observed without dissection. The functional kidney in the zebrafish is the pronephros, a simplified organ structure with only two nephrons and the glomeruli fused at the midline, containing a full range of cell types typical of kidneys in higher vertebrates.

This zebrafish proteinuria model enables us to screen for novel genes in the pathogenesis of renal and vascular disease and identify targets for drug development. Genes of interest are knocked down in zebrafish embryos and effects are analyzed in proteinuria. To further analyze the molecular mechanisms of proteinuria we use transgenic GFP-zebrafish, cell culture, confocal microscopy and electron microscopy.

With this high throughput assay system we can examine the effects of genetic disruption on the barrier function in the pronephros. We are able to successfully screen for genes that are promising candidates in loss-of-function experiments in mice. We inject fluorescence labeled dextrans and monitor the fluorescence intensity over time in the retinal vessel area. In addition, we perform detailed analysis with electron microscopy using transgenic fish with a green fluorescent protein labeled pronephros. To further analyze novel therapeutic targets for renal disease, we are collaborating with Ron Korstanje and his lab group at the Jackson Laboratory. This collaboration allows us to use mice as a second animal model and translational tool for the development of novel therapies.

Additionally, we are especially interested in the protein kinase C (PKC) family.  We have found that PKC isoforms play an important role in diabetic nephropathy, transplantation, and inflammation. We are now analyzing the role of PKC epsilon, theta, and zeta in our zebrafish model. In addition, we are studying the effects of environmental toxins on proteinuria in the zebrafish model.

Our model system together with our collaborators at the Jackson Laboratory and at Maine Medical Center and Maine Medical Center Research Institute in Portland is the basis for the reMAINE Healthy collaboration.

Program in Clinical Partnerships

This project has further spurred a larger statewide initiative called reMAINE Healthy, a new clinical research partnership between scientists at the MDI Biological Laboratory and The Jackson Laboratory, and physicians and patients at the Maine Medical Center (MMC) in Portland and Maine Medical Center Research Institute (MMCRI).

ReMAINE Healthy is a bench-to-bedside translational research program on genes and mechanisms for the early detection of chronic kidney disease and End Stage Renal Disease. This program will take laboratory discoveries in animal models and “translate” them into new clinical tools for diagnosing and preventing kidney disease in humans. The reMAINE Healthy program will use novel zebrafish models, genetic mouse models and samples from a patient cohort with chronic kidney disease for a translational research program in renal disease.

Chronic kidney disease affects 26 million adults, and over $42 billion is spent annually treating patients with this disease in the United States. It is a major diagnostic challenge, as people with early stages of the disease tend not to have any symptoms. The most common causes of chronic kidney disease are diabetes and hypertension. The aim of this collaboration is to identify novel molecules important in the pathophysiology of renal disease, which can serve as therapeutic targets or diagnostic tools to prevent chronic kidney disease.

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MDI Biological Laboratory Establishes Scientific Innovation Fund
BioIT World · May 21, 2018

MDI Biological Laboratory Names New President
Mount Desert Islander · May 11, 2018

MDI Biological Laboratory Names New President
Bangor Daily News · May 11, 2018

MDI Biological Laboratory Names New President
Bio-IT World · May 10, 2018

MDI Biological Laboratory Has a New President
Mainebiz · May 10, 2018

MDI Biological Laboratory Names New President
Press Release · May 10, 2018

Novel Nuclear Medicine Test Can Identify Kidney Transplant Infection
EurekAlert! · November 9, 2017

The Art of Diagnosis: Recognizing Disease in Paintings
Breaking Through · August 11, 2017

Report from the 2016 American Society of Nephrology Kidney Week: Using Stem Cells and Organoids to Build a New Kidney
Breaking Through · June 19, 2017

Introduction to the MDI Biological Laboratory’s Center for Science Entrepreneurship
Regenerative Medicine Network · March 7, 2017

Seeking to Regenerate a Kidney from Scratch
Breaking Through · January 9, 2017

Seeking to Regenerate a Kidney from Scratch: An Interview with Professor Hermann Haller, M.D.
Regenerative Medicine Network · January 5, 2017

Limb and Organ Regeneration Featured on "Maine Calling," MPBN's Popular Radio Call-In Program
Breaking Through · July 27, 2016

Human Limb and Organ Regeneration
MPBN · July 27, 2016

‘How to Make a New Kidney’ Is Subject of MDI Science Café
Press Release · July 25, 2016

Pharmacological targeting of actin-dependent dynamic oligomerization ameliorates chronic kidney disease in diverse animal models. Schiffer M, Teng B, Gu C, Shchedrina VA, Kasaikina M, Pham VA, Hanke N, Rong S, Gueler F, Schroder P, Tossidou I, Park JK, Staggs L, Haller H, Erschow S, Hilfiker-Kleiner D, Wei C, Chen C, Tardi N, Hakroush S, Selig MK, Vasilyev A, Merscher S, Reiser J, Sever S. Nat Med. 2015 Jun;21(6):601-9. doi: 10.1038/nm.3843. Epub 2015 May 11.

Baroreflex Activation Therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial. Bakris GL, Nadim MK, Haller H, Lovett EG, Schafer JE, Bisognano JD. J Am Soc Hypertens. Feb 14, 2012.

Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, Mimran A, Rabelink TJ, Ritz E, Ruilope LM, Rump LC, Viberti G; N Engl J Med. Mar 10; 364 (10): 907-17, 2011.

Cofilin-1 inactivation leads to proteinuria–studies in zebrafish, mice and humans. Ashworth S, Teng B, Kaufeld J, Miller E, Tossidou I, Englert C, Bollig F, Staggs L, Roberts IS, Park JK, Haller H, Schiffer M. PLoS One. Sep 8; 5 (9): e12626, 2010.

Determinants of urinary albumin excretion within the normal range in patients with type 2 diabetes: the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study. Ritz E, Viberti GC, Ruilope LM, Rabelink AJ, Izzo JL Jr, Katayama S, Ito S, Mimran A, Menne J, Rump LC, Januszewicz A, Haller H. Diabetologia. Oct 30, 2009.

Inhibition of protein kinase C in diabetic nephropathy–where do we stand? Menne J, Meier M, Park JK, Haller H. Nephrol Dial Transplant. Jul: 24(7): 2021-3, 2009.

Rapid screening of glomerular slit diaphragm integrity in larval zebrafish. Hentschel DM, Mengel M, Boehme L, Liebsch F, Albertin C, Bonventre JV, Haller H, Schiffer M. Am J Physiol Renal Physiol. Nov: 293(5):F1746-50, 2007.

Deletion of protein kinase C-epsilon signaling pathway induces glomerulosclerosis and tubulointerstitial fibrosis in vivo. Meier M, Menne J, Park JK, Holtz M, Gueler F, Kirsch T, Schiffer M, Mengel M, Lindschau C, Leitges M, Haller H. J Am Soc Nephrol. Apr: 18(4):1190-8, 2007.

Deletion of protein kinase C-beta isoform in vivo reduces renal hypertrophy but not albuminuria in the streptozotocin-induced diabetic mouse model. Meier M, Park JK, Overheu D, Kirsch T, Lindschau C, Gueler F, Leitges M, Menne J, Haller H. Diabetes. Feb: 56(2): 346-54, 2007.

Nephrin loss in experimental diabetic nephropathy is prevented by deletion of protein kinase C alpha signaling in-vivo. Menne J, Meier M, Park JK, Boehne M, Kirsch T, Lindschau C, Ociepka R, Leitges M, Rinta-Valkama J, Holthofer H, Haller H. Kidney Int. Oct: 70(8):1456-62, 2006.

Nephrogenesis is induced by Partial Nephrectomy in the Elasmobranch Leucoraja erinacea. Elger M, Hentschel H, Litteral J, Wellner M, Kirsch T, Luft FC, Haller H. J Am Soc Nephrol. Jun: 14(6): 1506-18, 2003.

Recent PubMed Publications

In vivo and in vitro analysis of age-associated changes and somatic cellular senescence in renal epithelial cells. Berkenkamp B, Susnik N, Baisantry A, Kuznetsova I, Jacobi C, Sörensen-Zender I, Broecker V, Haller H, Melk A, Schmitt R – PLoS One. 2014;9(2):e88071

Invariant natural killer T cells are depleted in renal impairment and recover after kidney transplantation. Peukert K, Wingender G, Patecki M, Wagner S, Schmitt R, Ge S, Schwarz A, Kronenberg M, Haller H, von Vietinghoff S – Nephrol Dial Transplant. 2014 May;29(5):1020-8

View All Publications

Zebrafish (Danio rerio) are used as a proteinuria-screening model for identification of new genes relevant in development of chronic kidney disease and diabetic nephropathy. This model will enable us to gain a better understanding of glomerular kidney disease and the physiology of glomerular filtration.

Proteinuria is a hallmark of renal and cardiovascular disease and indicates acute and chronic damage to the vasculature. We developed a novel model system for proteinuria screening in developing zebrafish larvae using transgenic fish and fluorescent plasma protein to measure proteinuria in screening assays to analyze the molecular mechanisms of capillary permeability and to identify novel therapeutic targets to prevent proteinuria.

Students will learn to care for and breed zebrafish to test genes of interest for kidney disease using zebrafish as a screening model. They will learn microinjection in zebrafish embryos and then analyze results using light and confocal microscopy and prepare tissue samples for electron microscopy.

2012

Kelsey Ottmann

University: University of Maine at Farmington
MDI Biological Laboratory Program: Maine INBRE Undergraduate Program
Research Project: Zebrafish as a model system for podocyte injury in diabetic nephropathy and as a screening tool for identification of genes relevant in proteinuria development.

Cornelius Pauli

University: Hannover University, Hannover, Germany
MDI Biological Laboratory Program: Direct recruit to the Haller Laboratory
Research Project: Functional and histological analysis of kidney function after morpholino-induced knockdown of glycocalyx-associated genes in the zebrafish larval.

Pia Niggermann

High School: St. Ursula School, Hannover, Germany
MDI Biological Laboratory Program: Direct recruit to the Haller Laboratory
Research Project: Establish procedures for injecting zebrafish and analyzing test matings to establish a transgenic zebrafish colony.

Sophie Paschke

High School: Berlinisches School in Grauen Monastery, Berlin, Germany
MDI Biological Laboratory Program: Direct recruit to the Haller Laboratory
Research Project: Establish procedures for injecting zebrafish and analyzing test matings to establish a transgenic zebrafish colony.

2011

Astrid Gleaton

University: Bates College, Lewiston, Maine
MDI Biological Laboratory Program: Summer Research Fellowships for Undergraduates
Research Project: Further characterization of KMO in zebrafish using phenotype screening, eye assays and electron microscopy.

Henning Lassen

University: University of Osnabrück, Osnabrück, Germany
MDI Biological Laboratory Program: Direct recruit to the Haller Laboratory
Research Project: Establish protocols to create diabetic zebrafish by STZ antibiotic injections.

2010

Philipp Niggemann

High School: St. Ursula School, Hannover, Germany
MDI Biological Laboratory Program: Direct recruit to the Haller Laboratory
Research Project: Testing the effects of pH on zebrafish embryo development.

Daniel Claeys

High School: Kingston Grammar School, London, United Kingdom
MDI Biological Laboratory Program: Direct recruit to the Haller Laboratory
Research Project: Testing the effects of pH on zebrafish embryo development.

2009

Jeremy Quail

High School: High School for Mathematics, Science and Engineering, New York, New York
MDI Biological Laboratory Program: High School Research Fellowship Program
Research Project: Characterization of the gene Kynurenine-3-monooxygenase (KMO) in zebrafish

• Mario Schiffer, M.D.
• Jennifer Litteral, reMAINE Healthy Program Director
• Lynne Staggs, Lab Manager
• Pat Schroder, Ph.D., Research Assistant
• Nils Hanke, M.D.
• Susanne Fleig, M.D.
• Irini Tossidou, Ph.D.