Postdoctoral studies in Mitochondrial Stress and Ataxia in Friedreich’s disease and CYP2C19 Overexpression in the Fetal Brain (scholarship)

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The Section of Pharmacogenetics at Karolinska Institutet focuses on understanding the etiology and pathophysiology of central nervous system (CNS) disorders and uncovering genetic variations in drug metabolism, toxicity, and response. This research delves into mechanisms by which frataxin deficiency, characteristic of Friedreich’s ataxia, or fetal overexpression of the human CYP2C19 gene in mice cause cell damage, leading to anxiety and ataxia. In human overexpression of CYP2C19 is linked to depression and anxiety.

Friedreich’s ataxia is marked by progressive difficulties in swallowing and speaking, typically beginning between ages 20 and 25, and associated with cardiac and pancreatic dysfunction, culminating in heart failure, diabetes, and premature death. Overexpression of CYP2C19 in the mouse fetal brain correlates with increased risks of anxiety, depression, cerebellar injury, and ataxia in adulthood. Utilizing in vivo-like human liver cell models, conditional knockout mice, and transgenic mice, this research advances our understanding of these mechanisms.

The project

This project leverages advanced in vitro liver 3D systems and animal models to investigate therapies for reversing cellular damage caused by frataxin deficiency and less ataxia. Key objectives include:
1. In vitro studies: Employing 3D liver spheroid systems to explore the role of frataxin in ferrochelatase and IscU (Iron/sulfur cluster assemblern enzyme)-function and Fe-S cluster assembly and identify mechanisms behind. These liver models can also mimic liver pathologies, including hepatitis, steatosis, and fibrosis.
2. Analyses of FXN conditional KO mice: Analyses of morphology, gene expression and functional aspects of cerebelli from control and conditional FXN KO mice.
3. Drug screening: Identifying and validating therapeutic candidates that restore mitochondrial function and alleviate oxidative stress based on the in vitro models and validate their effects in the in vivo mouse models.
4. Comparison of the models. Analyze to what extent the transgenic CYP2C19 mice and those lacking cerebellar FXN expression in the cerebellum utilize the same mechanisms for inducing ataxia.

In a longer perspective we anticipate that knowledge from the project will facilitate treatment if Friedreich’s ataxia as well as other diseases including ataxia as a pathophysiological endpoint. The project is funded by the Swedish Brain Foundation and conducted in collaboration with the University of Belgrade’, Faculty of Pharmacy. While animal tissue is utilized, no live animal experimentation is required.

Duties

• Investigate the mechanistic role of frataxin deficiency and mitochondrial dysfunction and oxidative stress and possibilities for intervention.
• Evaluate the therapeutic potential of candidate molecules to be used in mouse models of ataxia.
• Perform advanced molecular and cellular analyses, including mRNA/protein quantification, imaging, and chemical intervention assays.

Your Profile

We seek a highly motivated candidate with:
• A doctorate (or equivalent) awarded within the past three years.
• Hands-on experience with cell culture, in vitro models, immunohistochemistry, imaging, Western blot, ELISA, PCR, and HPLC-MS.
• Good academic track record, including first-authored publications in peer-reviewed journals.
• Good communication and interpersonal skills for collaborative research in an English-speaking environment.

Entry requirements

Postdoctoral scholarships may be established for foreign researchers who pursue their merit in Sweden. The purpose of scholarships for postdoctoral qualification is to promote internationalization and contribute to research qualification after a doctorate or equivalent.

A scholarship for carrying out postdoctoral research can be granted for a maximum of two years within a four year period following the receipt of a doctoral degree or equivalent.

To be eligible for a postdoctoral scholarship, the person must have obtained a doctorate or a foreign degree deemed to be equivalent to a doctorate. Applicants who have not completed a doctorate at the end of the application period may also apply, provided that all requirements for a completed degree are met before the (intended) start date of the post doctoral education.

The head of the department determines whether their previous training and scholarly qualifications correspond to a Swedish doctorate or higher.

Location: Biomedicum, Campus Solna

Type of scholarship

The amount is tax free and it is set for twelve months at a time, paid out on a six months basis. In exceptional cases, shorter periods may be acceptable.

Application process

An application must contain the following documents in English or Swedish:

• A complete curriculum vitae, including date of the thesis defence, title of the thesis, previous academic positions, academic title, current position, academic distinctions, and committee work
• A complete list of publications
• A summary of current work (no more than one page)

The application is to be submitted on the Varbi recruitment system.

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