Ruprecht-Karls-Universität Heidelberg
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Simons0120 - Scientist (f/m) / PhD position
Project no:
Simons0120

Project leader:

Project supervisor:
Simons, Matias
Application deadline:
31. May 2020
Start of PhD project:
1. Jul 2020

Project description:

Title:
Role of proximal tubule protein uptake in the progression of proteinuric kidney disease
Summary:
The rate of chronic kidney disease is on the rise worldwide. Many forms of chronic kidney disease are featured by the loss of protein into the urine (proteinuria). When the cause of proteinuria lies within the glomerulus, such as in diabetic kidney disease, then the protein overload in the tubular lumen may lead to damage of the downstream tubular cells. Particularly vulnerable are proximal tubular cells (PTCs), because these cells are specialized in protein reabsorption and have a high metabolic demand. The large multiligand receptors megalin and cubilin, expressed at the apical surface of these cells, bind to and internalize >50 different plasma proteins. While megalin is a large transmembrane protein related to the low-density lipoprotein receptor, cubilin lacks a transmembrane domain and requires membrane anchoring via amnionless. The cytoplasmic domains of both megalin and amnionless contain NPXY motifs that engage the clathrin adaptor disabled-2 (DAB2) and mediate endocytosis of the filtered proteins into apical endocytic compartments. Interestingly, genome-wide association studies (GWAS) suggest that higher expression levels of DAB2 associate with decreased renal function in patients cohorts with chronic kidney disease. We therefore hypothesize that increased protein, in particular albumin, uptake through enhanced disabled-2 function promotes renal disease progression by impairing the PTC homeostasis.

The aim of this PhD project is to study the molecular mechanisms of disabled-2-mediated protein uptake in PTCs. For this, we will perform DAB2 knockout and overexpression in a variety of cell models. Apart from albumin uptake, we want to understand how disabled-2-mediated endocytosis contributes to the Wnt signaling pathway that has been shown to maintain terminal PTC differentiation and thereby protein uptake function. Ultimately, we also want test the protective role of DAB2 deficiency in proteinuric mouse models. Based on human genetic evidence, the project thus aims at a better understanding of PTC protein uptake and inhibition thereof as a therapeutic strategy in chronic kidney disease.
References:
1. Bedin M, Boyer O, Servais A, Li Y, Ahluwalia TS, Cambier A, Hogan J, Isnard-Bagnis C, Gribouval O, Morinière V, Tournant C, CKDGen Consortium, Bole-Feysot C, Jabot-Hanin F, Nitschké P, Köttgen A, Andersen CBF, Bergmann C, Antignac C, Simons M: High prevalence of C-terminal CUBN variants associated with chronic proteinuria and normal renal function in humans. Journal of Clinical Investigation, 2020 Jan 2;130(1):335-344.

2. Marchesin V, Pérez-Martí A, Le Meur G, Pichler P, Grand K, Klootwik ED, Kleta R, Lienkamp S, Simons M: Molecular basis for autosomal-dominant renal Fanconi syndrome caused by HNF4A. Cell Reports, 2019 Dec 24;29(13):4407-4421.

3. Simons M: The benefits of tubular proteinuria: an evolutionary perspective, Journal of the American Society of Nephrology, 2018 Mar;29(3):710-712.

4. Renal compartment-specific genetic variation analyses identify new pathways in chronic kidneydisease. Qiu C, Huang S, Park J, Park Y, Ko YA, Seasock MJ, Bryer JS, Xu XX, Song WC, Palmer M, Hill J, Guarnieri P, Hawkins J, Boustany-Kari CM, Pullen SS, Brown CD, Susztak K. Nat Med. 2018 Nov;24(11):1721-1731.

5. Dual roles for the adaptor protein Disabled-2 in embryonic developmet and kidney transport. Morris SM, Tallquist MD, Rock CO, Cooper JA. EMBO J. 2002 Apr 2;21(7):1555-64.
Methods that will be used:
Reprogrammed cell lines, renal organoids, mouse, Crispr/Cas9
Cooperation partners:
Christian Andersen, Aarhus University
Personal qualifications:
Qualified candidate should have a degree from an internationally accredited institution of higher education. Technical skills in molecular cloning, cell culture, confocal microscopy and mouse handling are desirable. Candidates are expected to be highly motivated and to work independently with a strong work ethic. Interest in interdisciplinary collaborations is highly desirable. We also invite applications from research-oriented MDs who want to do a PhD. Proficiency in English language is a requirement.
Keywords:
kidney, endocytosis, epithelial cells