Klotho and beta-Klotho (KLB) are obligatory co-receptors for a subset of fibroblast growth factors (FGFs) with endocrine functions. Mutations in Klothos or Fgf19, -21 or -23, or deregulation of their signalling are associated with altered metabolic physiology in a variety of human disorders with major impact on lifelong health and aging. Klotho is suggested to possess glycosidase activity although the exact nature of this remains to be established in vivo. We have recently identified the C. elegans Klotho orthologs and discovered that regulation of metabolic physiology by Klotho/FGFR is evolutionarily conserved from nematodes to mammals. Here we propose to use the genetically tractable C. elegans as a novel model to unravel the molecular mechanisms of Klotho/FGF as regulators of physiological homeostasis whilst replacing and reducing the use of vertebrate animals in research.
Specifically we will:
Identify the molecular interactions of Klotho/FGFR in metabolic physiology
Unravel the molecular mechanisms of Klotho/FGFR in metabolic physiology
Assess the evolutionary conservation of Klotho mode of action in vertebrate systems
C. elegans provides the ideal model to develop a better understanding of complex metabolic signalling networks at whole organism level. Given the recent discoveries of Klotho and FGF as regulators of key metabolic pathways, there is large pharma interest in this research area. Current animal models include mice and primates. This research will develop C. elegans as a model for Klotho/FGF studies. This project will further understanding of molecular mechanisms relevant to human health and ageing (including tissue calcification, chronic kidney disease and ageing-related syndromes). Furthermore, this research will uncover fundamental roles of Klotho/FGFR signalling in development, which will form the basis of generating new knowledge and therapeutic targets in tissue regeneration and ageing.
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Xu C et al. (2017). KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism. EMBO molecular medicine 9(10):1379-1397. doi: 10.15252/emmm.201607376