Project description
Adrenal organoids genetically engineered
The adrenal glands are a pair of small walnut-sized organs sitting on top of your kidneys. They produce hormones essential for regulating metabolism, the immune system, blood pressure and your response to stress among others. Adrenal gland malfunction (adrenal insufficiency) can be life-threatening. The GHSO project is developing a novel adrenal-like organoid, a 3D self-assembled cellular structure derived from human embryonic stem cells with capacity to produce adrenal hormones. Once this ground-breaking task is accomplished, GHSO will create adrenal organoids genetically engineered with common mutations to exhibit adrenal insufficiency. In parallel, the in vitro organoids will be implanted in vivo to assess its capacity to reverse the disease, accelerating the development of more effective treatments for adrenal insufficiency.
Objective
The adrenal cortex is essential for life; it is the primary site of steroid synthesis, producing glucocorticoids, which affect carbohydrate metabolism and mediate the mammalian stress response and mineralocorticoids, which control blood volume and salt homeostasis. Adrenal insufficiency (AI), which can be life threatening, is cause by a number of adrenal disorders, and lifelong management of these patients with exogenous steroids can be challenging. No drug suitably mimics the diurnal pattern of cortisol noted in healthy individuals, and objective variables to measure hormonal replacement therapy quality are lacking. The ability to generate steroid-producing cells from pluripotent stem cells through cell reprogramming, a process where a specialized cell type is induced to transform into a different cell, offers a new paradigm for functional studies, modelling human disease and drug testing and eventually can be used as a cell source for cellular therapies for patients suffering from adrenal conditions. This proposal aims to develop methodologies to generate adrenal-like organoids from human embryonic stem cells (hESCs), which have not been generated so far, without requiring overexpression of exogenous transcription factors and test them in in vivo models of adrenal insufficiency. Because small molecules provide several distinct advantages in controlling protein functions (e.g. temporally controllable, reversible, tunable and tractable) I will utilize them for a faster, more efficient, and directed cellular reprogramming. CRISPR-Cas9 genome engineered steroid-producing organoids harbouring common mutations found in congenital adrenal hyperplasia (CAH), the most common type of AI, will be generated and used as a disease modelling platform to study CAH. This proposal aims to accelerate the translation of this promising bench research to patients affected by adrenal insufficiency over the next 10 years.
Fields of science
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencesbiological sciencesgeneticsmutation
- natural sciencesbiological sciencesbiochemistrybiomoleculescarbohydrates
- natural sciencesbiological sciencesgeneticsgenomes
- medical and health sciencesbasic medicinephysiologyhomeostasis
Programme(s)
Funding Scheme
MSCA-IF-GF - Global FellowshipsCoordinator
01069 Dresden
Germany