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Funded Projects

Our research is supported by several national and international funding agencies. We are part of the Collaborative Research Centers (CRC) 1453 [2021-2024], 992 [2020-2024] and 1479 [2021-2025] of the German Research Foundation at the University of Freiburg, Germany (https://www.sfb1453.uni-freiburg.dehttp://www.sfb992.uni-freiburg.de). These CRCs aim to understand mechanisms underlying complex (epi)genetic diseases and generate optimal synergies with the work carried out in the Institute of Genetic Epidemiology.

German Research Foundation (CRC 1453 “Nephrogenetics (NephGen)”): Speaker; Projects P15, P16, S1; 2021-2024

Kidney disease represents a global public health challenge. Chronic kidney disease alone affects 10-15% of adults, and kidney cancers add to this burden. Despite the high prevalence and the great costs associated with treating kidney diseases, the low number of clinical trials and specific treatments in nephrology attests to a shortage of therapeutic targets. The identification of druggable targets has been complicated by an incomplete understanding of the underlying mechanisms. Pharmacological compounds that operate on proteins or pathways connected to a given disease by human genetic evidence are twice as likely to successfully move through the clinical development pipeline, compared to those with no genetic support. Therefore, NephGen will use evidence from both monogenic and complex genetic kidney diseases to identify and characterize molecules and pathways that represent targets to improve the prevention and treatment of kidney disease. To this end, NephGen researchers have assembled large patient- and population-studies, and established a variety of model organisms and state-of-the-art methods for genome editing, (single-cell) sequencing, structural biology, diverse omics technologies, whole animal live imaging as well as integrative analyses and modeling of high-dimensional data. To facilitate clinical translation, NephGen will use both modern statistical approaches and modify the implicated molecules and pathways in disease-specific model organisms through genetic and pharmacological approaches. 

More information can be found here: https://www.sfb1453.uni-freiburg.de

German Research Foundation (CRC 1479 „OncoEscape – Oncogen-driven immune escape“): Project S1 „Data analysis, integration, and modelling“, 2021-2025; together with Prof. M. Boerries and Prof. O. Schilling

Summary: S1 will provide standardised and advanced workflows for the analysis of next generation sequencing (NGS) data of human tumour samples for oncogenic mutations and scRNA-seq data of immune and tumour cells derived from primary human tumour samples as well as quantitative and functional proteomics workflows and data analyses for human tumour samples. Besides its focus on project support, S1 also aims to identify metabolite biomarkers of immune cell function and to develop novel proteomics analysis methods.

 

German Research Foundation (SE 2407/3-1): „Discovery and Characterization of Risk Factors for Chronic Kidney Disease Progression, Cardiovascular Diseases and Death”, 2021-2023

Utilizing the data available from the German Chronic Kidney Disease (GCKD) study, we thus aim to assess baseline metabolite levels and their ability to predict adverse outcomes in chronic kidney disease (CKD) patients as well as to model CKD progression in the presence of non-fatal events. The three specific objectives in this project are:

(1) To evaluate associations of metabolite levels from plasma and urine with the prospective endpoints all-cause mortality, KF, and CV events. We expect to find known as well as novel associations.

(2) To evaluate the prognostic value of selected endpoint-associated metabolites, while accounting for known prognostic factors. The performance will be compared in relation to the performance of clinical benchmark models. An external validation step using independent data is pursued.

(3) Finally, we will explore the specific effects of non-fatal events such as MI or AKI on KF risk using the statistical framework of multi-state models. 

German Research Foundation (KE 2513/1-1 | KO 3598/6-1): „Identification and Characterization of Novel Imaging Biomarkers of Kidney Function and Disease ”, 2019-2022

The overarching goal of the project is to identify and characterize novel MR imaging biomarkers of kidney function and disease in order to lay the foundation for improved diagnosis, prediction and etiological research of chronic kidney disease (CKD), an important clinical and public health problem and of its associated comorbidities such as cardiovascular disease and death. This goal will be achieved through four scientific aims:

  1. Identification and quantification of MR imaging biomarkers of kidney function and characterization of their population distributions in the German National Cohort (GNC) study

  2. Correlation of newly identified MR imaging biomarkers with established markers of kidney function and disease and use in diagnosis of CKD in the GNC

  3. Deep convolutional networks to derive integrative MR imaging biomarkers of kidney function and comparison to traditional markers of kidney function in GNC

  4. Evaluation of newly identified MR imaging biomarkers of clinically referred patients and implementation of a pilot decision support system

The different aims build on each other, and are connected via feedback loops. They will be addressed by two multi-disciplinary groups (Radiology, Epidemiology), jointly working on each aim.

EU Marie Sklodowska Curie Training Network TRAINCKDis (Multidisciplinary Training in Chronic Kidney Disease: from genetic modifiers to drug discovery)

The goal of the Research Training Network TrainCKDis is to provide high-level training in chronic kidney disease (CKD) - a global public health burden - to a new generation of highly achieving early stage researchers. TrainCKDis will develop scientific skills necessary for thriving careers in an expanding area that underpins innovative technological development across a range of diverse disciplines including nephrology, epidemiology, genetics, cell biology, and drug discovery at the interface of basic molecular, genetic and clinical research. This will be achieved by a unique combination of “hands-on” research training, non-academic placements, courses and workshops on scientific and transferable skills, facilitated by the consortium’s academic/non-academic composition. The EU Training Network is coordinated by Dr. Fabiola Terzi at the Université Paris Descartes.

Bundesministerium für Bildung und Forschung (e:Med Juniorverbünde in der Systemmedizin): CKDNapp A toolbox for monitoring and tailoring treatment of chronic kidney disease patients - a personalized systems medicine approach, 2020-2024

Summary: Chronic Kidney Disease (CKD) can arise from multiple causes. It is characterized by a variable course of diseases and a high burden of cardiovascular and metabolic comorbidities, complicating optimal treatment. To provide optimal, personalized medical care for each patient, physicians need to obtain a detailed, comprehensive picture of that patient’s state. For this purpose, he/she integrates different levels of data, e.g., clinical/demographic parameters, biomarkers, and drug information, with medical knowledge. Because CKD is a complex disease, this data integration process is extremely challenging.

We (collaboration partners: Ulla T. Schultheiß, Helena U. Zacharias, Michael Altenbuchinger und Johannes Raffler) propose based on data from the German Chronic Kidney Disease study (1) to computationally model this complex CKD system, (2) to enrich these models with novel omics data, (3) to discover novel biomarkers, and (4) to build a clinical decision support (CDS) software based on these models assisting physicians in personalized everyday CKD patient care. Our CDS software, called CKDNapp (CKD Nephrologists’ app), will (i) predict adverse events and disease progression, (ii) refine diagnosis of CKD staging, (iii) return transparent reasoning for all predictions and recommendations, (iv) offer in silico modification of patient parameters by the physician, and (v) deliver comprehensive literature support. It will be available as an easy-to-use software for smartphones, tablets, and desktop computers.

Subcontract to “Identifying Novel Biological Pathways for Gout using DNA Methylation and Genetics”, NIAMS R01-AR073178 (to Dr. Adrienne Tin, PI), 2018-2023

Summary: Gout is the most common form of inflammatory arthritis. The incidence and prevalence of gout and its public health importance are all rising. The overarching goal of this study is to uncover epigenetic factors that can illuminate the biological pathways underlying gout susceptibility and/or serve as biomarkers for the prediction of gout for risk stratification to improve gout management. This will be accomplished using a combination of approaches that investigate (1) the association of differentially methylated DNA sites in blood and incident gout in prospective cohort studies; (2) whether differential DNA methylation likely represents a cause or consequence of disease using Mendelian randomization, and (3) the development and validation of risk prediction models for gout incorporating epigenetic risk factors. This project will accelerate research on gout prevention and treatment by identifying potentially reversible epigenetic factors related to incident gout, and will lay the foundation for risk stratification strategies for patients with gout or at high risk for gout.

German Research Foundation (CRC 992 “MEDEP: Medical Epigenetics”): Project C07 “Role of DNA methylation in human chronic kidney disease”, 2020-2024

Summary: Chronic kidney disease (CKD) is a complex disease affecting ~10% of adults and has a clear heritable component. Small cohort human and animal studies have linked altered DNA methylation to CKD. Therefore we will carry out epigenome-wide association studies (EWAS) of incident CKD and EWAS of CKD progression among patients with specific CKD etiologies. This will be followed by integration of results with kidney cell-type specific gene expression and chromatin annotation maps and genome-wide DNA sequence variants. Together, these approaches will provide new insights into the contribution of epigenetic modifications to CKD in humans.

Previously funded projects

German Research Foundation (KO 3598/4-2): “Renal Metabolite Handling: from Gene to Function to Disease”, 2019-2022

Summary: The risk for complex diseases such as chronic kidney disease (CKD) is influenced both by the environment and risk variants in many genes, as well as their interplay. Many complex diseases are common and thus represent a large public health burden. Recent breakthroughs using high-throughput –omics techniques have led to fundamental new insights recognizing the role of genetic and metabolic variation in the pathogenesis of many human complex diseases. Yet, the exact genes and metabolic changes contributing to complex disease susceptibility and their underlying pathophysiological mechanisms of action mostly remain unclear.

This project addresses these knowledge gaps: it tests the hypotheses that variation in metabolite handling contributes to the complex disease CKD and that underlying processes can be uncovered by the systematic integration of human genetic and metabolic variation, the modeling of organ-specific functions, and functional and epidemiological follow-up studies. This will be accomplished through four steps:

  1. In the first step, genome-wide association studies of concentrations of a wide variety of metabolites in serum and urine of CKD patients participating in the German Chronic Kidney Disease Study will be conducted. Significant associations between genetic variants and metabolite concentrations will systematically allow for the identification of novel genes connected to the handling of the respective metabolite.
  2. For significantly associated genetic variants, the modeling of kidney-specific functions from the metabolite data will help to prioritize genes for follow-up experiments addressing their putative function. For example, an association with the fractional excretion of the specific metabolite may suggest that the gene encodes for a transport protein of that metabolite.
  3. Prioritized genes from steps 1 and 2 will be subjected to functional investigations in experimental models such as transport experiments in Xenopus oocytes.
  4. Identified metabolites will be evaluated with respect to their role across different etiologies of CKD and for their potential to predict CKD progression as well as death among 5,217 participants of the German Chronic Kidney Disease Study, the largest prospective study of CKD worldwide.

The proposal extends beyond standard genome-wide association studies and has the potential to generate important novel insights. Feasibility is ensured because it builds on established resources, including a large prospective study with available biosamples and genome-wide marker genotypes. The innovative and multi-disciplinary approach addresses the fundamental question how individual genetic and metabolic variation can be systematically used to understand general pathophysiological mechanisms underlying CKD and other complex diseases in the population.

German Research Foundation (KO 3598/5-1): Heisenberg Professorship of Genetic Epidemiology

Summary: The goal of the Professorship is to consolidate an independent research program in Genetic Epidemiology at the University of Freiburg. The program focuses on the design and conduct of epidemiological studies and the analysis of the resulting data to generate novel insights into complex disease genetics.

German Research Foundation (CRC 1140 “KIDGEM: Kidney Disease – From Genes to Mechanisms”): Project A05 “Genetic risk variants for chronic kidney diseases in a prospective cohort of 5,217 patients”, 2015-2019

Summary: Membranous nephropathy (MN) and focal-segmental glomerulosclerosis (FSGS) are the most common causes for nephrotic syndrome in adults, a hallmark of glomerular diseases. This project aims to address important knowledge gaps about their genetic architecture in a large, prospective study of 5217 patients with chronic kidney disease (CKD), the German Chronic Kidney Disease (GCKD) Study. As part of our work program, we will first conduct genome-wide association studies at unprecedented coverage examining >10 million common genome-wide SNP markers per person, to map risk genes and refine risk variant associations for MN, FSGS and all-cause CKD. Moreover, we will carry out the first examination of >250,000 rare missense, splice and stop mutations discovered through whole exome sequencing to identify potentially causal mutations for MN, FSGS and all-cause CKD. Validated risk variants will be examined for their combined effect and for interactions with each other and environmental exposures, capitalizing on the detailed information about medication intake and the in-depth clinical and biochemical profiles available in GCKD. Genome-wide searches for effect modifiers will also be carried out. Specificity of identified risk variants for MN or FSGS vs. their generalizability to other CKD etiologies will be assessed by examination of effects across the many CKD etiologies represented in the GCKD Study. Lastly, risk variants will be evaluated for their association with CKD progression (kidney function decline, incident ESRD) and complications (cardiovascular events, mortality) using methods for prospective data analysis. These studies will be complemented by genome-wide searches for variants that may be associated with disease progression rather than disease development. The prospective nature of the GCKD Study allows for the evaluation of the identified risk variants as diagnostic and especially prognostic markers. In addition to a better understanding of the genetic architecture of MN, FSGS and all-cause CKD, this work can generate novel insights about the physiology of glomerular kidney diseases. The generation of genome-wide association statistics from thousands of CKD patients will provide a valuable resource for the targeted investigation of human genes studied in other KIDGEM projects.

KfH Stiftung Präventivmedizin: The German Chronic Kidney Disease (GCKD) Study, 2009-2019

Summary: The Stiftung Präventivmedizin of the Kuratorium für Heimdialyse supports the multi-centric observational prospective GCKD Study. This study enrolled 5,217 patients with chronic kidney disease across Germany and now follows the patients over 10 years to assess disease progression and renal and cardiovascular endpoints. Freiburg is one of nine study centers, in which team members of the Division of Genetic Epidemiology and the Department of Internal Medicine IV at the Medical Center of the University of Freiburg work together to carry out the study visits and follow-up. More information on the study can be found here: http://www.gckd.de/

Else Kröner Forschungskolleg NAKSYS (Nierenfunktionsstörungen als Komplikation von Systemerkrankungen): Project 08 Relationship of Thyroid Function and Chronic Kidney Disease, 2015-2020

Available in German

Subcontract to “Epigenetic Landscape of Chronic Kidney Disease”, NIDDK 5R01DK087635-07 (to Dr. Katalin Susztak, PI), 2014-2019

Summary by the PI: Genome wide association studies (GWAS) have been extremely powerful and successful identifying associations between genetic polymorphisms (SNP) and diabetic and chronic kidney disease (CKD) development. Our next big challenge is to translate this information to understand the mechanism of diabetic and CKD development. The major hurdle is that the majority of CKD associated polymorphisms lie outside the coding region of the genome. Therefore classic protein biochemistry and gene deletion studies of model organisms cannot yet be applied. Several recent pioneering studies have provided a novel framework for such experiments and indicate that the cell type specific epigenome can be used to understand and annotate the non-coding region of the genome. As there are hundreds of established SNPs for CKD, performing individual experiments for each SNP could be a daunting task, therefore there is a critical need for genome wide cell type specific mapping of non-coding regulatory regions and defining the correlation between SNP's and transcript levels. The proposal will use a combination of methods to dissect the association between diabetic and chronic kidney disease associated polymorphisms and disease.

German Research Foundation (KO 3598/3-1): Heisenberg Professorship, 2016-2018

Summary: The goal of the Professorship is to establish an independent research program in Genetic Epidemiology at the University of Freiburg. The program focuses on the design and conduct of epidemiological studies and the analysis of the resulting data to generate novel insights into complex disease genetics.

German Research Foundation (KO 3598-4/1): “Renal Metabolite Handling: from Gene to Function to Disease”, 2014-2018

Summary: The risk for complex diseases such as chronic kidney disease (CKD) is influenced both by the environment and risk variants in many genes, as well as their interplay. Many complex diseases are common and thus represent a large public health burden. Recent breakthroughs using high-throughput –omics techniques have led to fundamental new insights recognizing the role of genetic and metabolic variation in the pathogenesis of many human complex diseases. Yet, the exact genes and metabolic changes contributing to complex disease susceptibility and their underlying pathophysiological mechanisms of action mostly remain unclear.

This project addresses these knowledge gaps: it tests the hypotheses that variation in metabolite handling contributes to the complex disease CKD and that underlying processes can be uncovered by the systematic integration of human genetic and metabolic variation, the modeling of organ-specific functions, and functional and epidemiological follow-up studies. This will be accomplished through four steps:

  1. In the first step, genome-wide association studies of concentrations of a wide variety of metabolites in serum and urine of CKD patients participating in the German Chronic Kidney Disease Study will be conducted. Significant associations between genetic variants and metabolite concentrations will systematically allow for the identification of novel genes connected to the handling of the respective metabolite.
  2. For significantly associated genetic variants, the modeling of kidney-specific functions from the metabolite data will help to prioritize genes for follow-up experiments addressing their putative function. For example, an association with the fractional excretion of the specific metabolite may suggest that the gene encodes for a transport protein of that metabolite.
  3. Prioritized genes from steps 1 and 2 will be subjected to functional investigations in experimental models such as transport experiments in Xenopus oocytes.
  4. Identified metabolites will be evaluated with respect to their role across different etiologies of CKD and for their potential to predict CKD progression as well as death among 5,217 participants of the German Chronic Kidney Disease Study, the largest prospective study of CKD worldwide.

The proposal extends beyond standard genome-wide association studies and has the potential to generate important novel insights. Feasibility is ensured because it builds on established resources, including a large prospective study with available biosamples and genome-wide marker genotypes. The innovative and multi-disciplinary approach addresses the fundamental question how individual genetic and metabolic variation can be systematically used to understand general pathophysiological mechanisms underlying CKD and other complex diseases in the population.