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MIND-NHE6

Financiado

Molecular Insights into human NHE6: From Dimerization to Disease Implications

The human Na+/H+ exchanger 6 (HsNHE6) is crucial for regulating pH in recycling endosomes in the central nervous system. Mutations in HsNHE6 are linked to Christianson syndrome (CS), a severe neurodevelopmental disorder. However,... ver más

31/10/2026

UCPH

215K€

Presupuesto del proyecto: 215K€

Líder del proyecto

KOBENHAVNS UNIVERSITET No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Financiación concedida El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2024-04-11

HORIZON-MSCA-2023-PF-01-01: MSCA Postdoctoral Fellowships 2023 ExpectedOutcome:Project results are expected to contribute to the following outcomes:

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1 Participantes

UCPH

214.93K€ | Lider

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Duración del proyecto: 30 meses Fecha Inicio: 2024-04-11
Fecha Fin: 2026-10-31

Líder del proyecto

KOBENHAVNS UNIVERSITET No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 215K€

Descripción del proyecto The human Na+/H+ exchanger 6 (HsNHE6) is crucial for regulating pH in recycling endosomes in the central nervous system. Mutations in HsNHE6 are linked to Christianson syndrome (CS), a severe neurodevelopmental disorder. However, the molecular mechanisms underlying HsNHE6 ion transport and its dysfunction due to CS mutations remain elusive. My research aims to bridge this knowledge gap by combining cellular and liposomal functional assays and single-particle cryo-electron microscopic structural investigations of HsNHE6. I will explore how dimerization in the lipid environment influences its ion transport mechanism, how the dimer functions as a whole, and how CS-associated mutations affect both dimerization and ion transport. I will conduct functional assays on heterodimeric HsNHE6, composed of wild-type (WT) and transport-deficient protomers, complemented by structural investigations to uncover the structure-function relationship during ion transport. I will identify HsNHE6-bound lipids and analyze HsNHE6 structure in its native environment utilizing detergent-free extraction. Furthermore, I will perform functional assessment in various lipid environments to unravel how the lipid environment influences dimerization and ion transport. Additionally, I aim to investigate whether and how CS-associated mutations lead to a loss-of-function phenotype and can exert a dominant-negative effect on a WT protomer by integrating functional assays with structural analyses of CS-mutant HsNHE6. The project aims to unravel the molecular mechanisms governing ion transport of HsNHE6 within the lipid bilayer and will provide insights into the molecular basis of CS. By integrating functional and structural data, it offers the potential to guide therapeutic targeting of HsNHE6 in the context of CS. The project is hosted at the Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, under the supervision of Assoc. Prof. Henriette E. Autzen.

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