Project

Back to overview

Biochemistry and neuropathophysiology of tetrahydrobiopterin metabolism and deficiencies

English title Biochemistry and neuropathophysiology of tetrahydrobiopterin metabolism and deficiencies
Applicant Blau Nenad
Number 107500
Funding scheme Project funding
Research institution Abteilung für Klinische Chemie und Biochemie Kinderspital Universitäts-Kinderkliniken Zürich
Institution of higher education University of Zurich - ZH
Main discipline Biochemistry
Start/End 01.04.2005 - 31.03.2008
Approved amount 296'000.00
Show all

Keywords (6)

INHERITED METABOLIC DISEASE; 6-PYRUVOYL-TETRAHYDROPTERIN SYNTHASE; CENTRAL NERVOUS SYSTEM; TRANSGENIC MICE; blood-brain barrier; selective screening

Lay Summary (English)

Lead
Lay summary
The objective of this project is to discover through a series of experiments and collaborative efforts the underlying mechanisms by which BH4 regulates phenylalanine and neurotransmitter homeostases as well as nitric oxide synthase (NOS) activity in different cells. So far the patients with inherited BH4 deficiency were investigated as a model to study the function and therapeutic efficiency of BH4 as well as the phenotype-genotype correlation. A recently discovered group of BH4-responsive phenylalanine hydroxylase-deficient patients open a new option for the pharmacological treatment of phenylketonuria (PKU). The present research project will focus on our major efforts in the molecular understanding of BH4 deficiency by generating the transgenic mice and it will cover the following topics: 1) Molecular analysis of patients’ fibroblasts including mutation analysis and recombinant expression of BH4 pathway genes; 2) Targeted mutagenesis of the mouse BH4 genes by homologous recombination in embryonic stem cells (knock-in or conditional knock-out); 3) Regulation of aromatic amino acid hydroxylases by BH4 and implication to BH4-responsive PKU; 4) Regulation BH4 biosynthesis in primary and immortalized human cell lines by BH4 and phenylalanine and influence of cytokines; 5) Blood-CSF and blood-brain barrier transport of BH4 derivatives.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
66953 Biochemistry and neuropathophysiology of tetrahydrobiopterin metabolism and deficiencies 01.04.2002 Project funding
119982 Biochemistry and neuropathophysiology of tetrahydrobiopterin metabolism and deficiencies 01.04.2008 Project funding

-