Contact term: This is a full-time, fixed term (2-year) position on Crick terms and conditions of employment.
Ultanir's laboratory studies the roles of protein kinases in neuronal development and function. Kinases regulate numerous cellular processes by phosphorylating their substrates.
A major focus in the lab is understanding the functions of a serine/threonine kinase called CDKL5. CDKL5 is highly expressed in the brain. Loss of function mutations in CDKL5 cause a neurodevelopmental disorder with early-onset seizures and profound neurological defects, termed CDKL5 deficiency disorder (CDD). Patients with CDD require life-long care. There are no disease targeting therapies for CDD. We identified several phosphorylation substrates of CDKL5 in the developing brain and defined their roles (PMID 38081835, 30266824 & Lopes et al, BioRxiv, 2024). Using these phosphorylations as read-outs of CDKL5 activity, we demonstrated that CDKL2, a kinase similar to CDKL5, can phosphorylate common substrates with CDKL5 (PMID 38326557). CDKL5 is on the X chromosome leading to mosaic expression in patients. CDKL2 is broadly expressed in neurons. Increasing CDKL2 expression can therefore be a therapeutic avenue.
The Isalan lab has long worked on a zinc finger engineering platform for gene therapy (PMID 11433278, 23054839, 27600816). Zinc finger proteins (ZFPs) can be engineered to make tools to control genes via viral vector delivery, especially using adeno-associated viruses (AAVs; 35223884). The ZFP modular platform drives robust activation or repression of target genes. Since many zinc fingers have human origins, they can be delivered long-term to patients without causing a strong immune response.
In this project, we aim to develop ZFPs which can upregulate CDKL2 mRNA expression and test if these can rescue molecular, cellular and behavioural defects in CDKL5 deficiency models. The postdoctoral researcher will generate and test zinc finger protein transactivators. They will then use CDKL5 knockout mouse models to determine if they can restore CDKL5-mediated functions at the molecular and behavioural level. iPSC derived neurons of CDD models will also be used to test rescue of phosphorylation substrates. The postdoctoral researcher will lead their own projects, contribute to other projects on a collaborative basis, and help train PhD students.
Key experience and competenciesThe post holder should embody and demonstrate our core Crick values:
Bold; Open; Collegial PhD in biology, biochemistry, neuroscience or a related discipline or in the final stages of PhD submissionGood knowledge of molecular biology skillsTrack record of writing papers as evidenced by publications or submitted manuscripts in referred journalsEvidence of data presentation at scientific meetingsExperience in research with iPSC derived neuronsExperience in RNA sequencingExperience in mass spectrometryExperience in neonatal brain injections or in utero electroporationsExperience in mouse behavioural analysisAbout Us
At the Crick, we conduct research at the forefront of biomedical research. We combine rigour with an open and collaborative culture, and are outward-looking, reflecting our status as a partnership of six organisations aiming to pool knowledge, ideas and resources.
We have a wide research portfolio with no divisions or departments, bringing biomedical researchers together with clinicians, physical scientists and applied scientists from our pharmaceutical partners.
We aim to attract the most talented researchers and support them to tackle innovative research questions. Our science technology platforms provide our researchers with access to state-of-the-art technology and expertise.
We provide an excellent learning environment with dedicated education programmes in public engagement with science, education and personal development, and a postdoc training programme that prepares scientists for leadership roles in science.
If you are interested in applying for this role, please apply via our website.All offers of employment are subject to successful security screening and continuous eligibility to work in the United Kingdom.If you require a visa to work in the UK we will help support your application should you be successful.
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