Ruprecht-Karls-Universit├Ąt Heidelberg
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Rappold0119 - Scientist (f/m) / PhD position
Project no:
Rappold0119

Project leader:

Project supervisor:
Rappold, Gudrun
Application deadline:
20. Dec 2019
Start of PhD project:
1. Feb 2020

Project description:

Title:
Investigation of KCNQ1 function in human neurons with a specific focus on insulin signalling
Summary:
In this project we address insulin-related signaling as a novel key-modulator of comorbid mental and non-mental diseases. Dysregulation of insulin signaling has been implicated in multimorbidity across the lifespan, in particular in type 2 diabetes, metabolic syndrome, obesity, and Romano Ward Syndrome. More recently, altered insulin signaling has also been implicated in neurodegenerative brain disorders (dementias and Alzheimer disease) and is considered as a key-component of compulsivity-linked, neurodevelopmental disorders (obsessive compulsive disorder and autism spectrum disorders).
The integration of existing genetic/genomics data for obsessive compulsive disorder indicated that signaling cascades involved in the endogenous synthesis, secretion, and extracellular signaling of insulin in and around postsynaptic dendritic spines were central to the regulation of spine formation and of synaptic plasticity. This analysis revealed KCNQ1 as a key-molecule. KCNQ1 is a voltage-gated potassium channel that inhibits the secretion of insulin produced by neurons locally. The gene encoding KCNQ1 has been identified as a susceptibility gene for type 2 diabetes and first evidence for an association with Alzheimer disease has been found for a genetic variant in KCNQ1.
In this project we will investigate KCNQ1 function in human neurons, derived from induced pluripotent stem cells (iPSCs). KCNQ1-knockout iPSC lines will be generated using CRISPR/Cas-based genome editing. The iPSC lines will then be differentiated into neurons and morphological, molecular, and functional assays will be performed to analyse cell type composition, synaptic connectivity and neuronal differentiation properties, with a specific focus on insulin signaling. This allows us to delineate whether the loss of KCNQ1 results in changes in insulin-related mechanisms directly in human neurons. We will create an in vitro model of human neurons, which we can manipulate to delineate the causal mechanisms underlying insulin-related comorbidities.
References:
https://www.klinikum.uni-heidelberg.de/humangenetik/forschung/abt-molekulare-humangenetik
Methods that will be used:
Cell culture, genetic manipulation of iPSC cells with CRISPR-Cas system, molecular and biochemical methods, confocal microscopy, transcriptome and proteome analysis, calcium imaging
Cooperation partners:
Personal qualifications:
Master in molecular medicine, biology, biochemistry or related disciplines
Strong background in molecular or cell biology,
Experience in cell culture, especially with iPSCs and neuronal differentiation is desired
High motivation
Keywords:
Insulin signaling, human neurons, KCNQ1, autism, induced pluripotent stem cells, neuronal differentiation