Project description
Human embryonic stem cells as a source of growth hormone-releasing hormone neurons
Growth hormone-releasing hormone (GHRH) stimulates the pituitary gland to produce and release growth hormone (GH) into the bloodstream. GHRH is released by the neurosecretory nerve terminals in the arcuate nucleus of the hypothalamus in a pulsatile manner, stimulating similar pulsatile release of the GH. The mechanisms of GH regulation are poorly understood since hypothalamic GHRH neurons are virtually impossible to obtain for disease modelling. The goal of the EU-funded GHRH neurons project is to produce GHRH neurons by in vitro differentiation from self-renewable human embryonic stem cells. This project will provide a platform to model the genetic causes of GH deficiency with possible applications in human growth-modulating drug discovery.
Objective
Hypothalamic growth hormone-releasing hormone (GHRH) neurons stimulate pulsatile pituitary growth hormone (GH) secretion and thereby determine glucose homeostasis and growth in children and eventually adult height. Conversely, growth hormone deficiency is potentially lethal in neonates, and can lead to short stature and significant morbidity later in life. However, the mechanisms of growth hormone deficiency are incompletely understood, since pituitary cells and hypothalamic GHRH neurons are virtually impossible to obtain for disease modelling. The aim of my proposal is to differentiate GHRH neurons from human embryonic stem cells (hESCs), which can self-renew indefinitely in culture while maintaining the ability to become almost any cell type in the human body. My proposal is comprised of three distinct work packages (WP1-3). In WP1, I will develop a conventional growth factor-based protocol for GHRH neuron differentiation by taking advantage of the existing knowledge on signals regulating hypothalamic development. In WP2, I will use RNA sequencing data from WP1 to directly differentiate hESCs to GHRH neurons by CRISPR-dCas9-based gene activation system (CRISPRa), which can temporally control the transcription of desired endogenous loci. In WP3, I will characterize the endocrine and electrophysiological properties of GHRH cells from WP1 and WP2. My project will provide a platform to model genetic causes of GH deficiency, and is expected to be applicable for human growth-modulating drug discovery. The three WPs will be carried out in an excellent training environment at the Stem Cells and Metabolism Research Program at the Research Program Unit (research flagship program of the University of Helsinki, Finland).
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencesbiological sciencesgeneticsRNA
- medical and health sciencesbasic medicinephysiologyhomeostasis
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Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
00014 HELSINGIN YLIOPISTO
Finland