Research Projects
Functional characterization of β-Klotho in cardiometabolic diseases and biological ageing beyond its original role as a co-receptor for FGF19 and FGF21

Obesity and its associated metabolic disorders have become prominent public health challenges, underscoring an urgent need for the development of targeted therapeutic interventions. Extensive animal studies and clinical trials have demonstrated the therapeutic potential of fibroblast growth factor 21 (FGF21) in treating obesity-related conditions, notably hyperlipidemia and fatty liver disease. However, the issue of FGF21 resistance remains unresolved and the functioning mechanisms of FGF21 and its receptors remain incompletely understood.

Traditionally, FGF21 is believed to signal through a membrane-bound receptor complex comprising FGF receptor-1 (FGFR1) and the obligate co-receptor β-Klotho (KLB). Remarkably, our preliminary study identified two soluble forms of KLB (sKLB), a long form (~140 kDa) and a short form (~85 kDa). This project aims to (1) elucidate the mechanisms underlying sKLB generation, including identifying specific cleavage sites and proteolytic enzymes involved. We will also investigate how sKLB facilitates FGF21 trans-signaling. (2) We will employ multi-omics approaches to dissect the intracellular signaling networks activated by sKLB alone and in conjunction with FGF21, thereby uncovering the molecular effectors of sKLB/FGF21-mediated signaling. (3) We will quantify circulating sKLB levels in plasma samples from human cohorts with obesity-related conditions such as type 2 diabetes and fatty liver, utilizing our validated in-house ELISA kits. Parallel assessments in corresponding mouse models will help identify tissue sources and dynamics of circulating sKLB, with the goal of establishing sKLB as a novel biomarker for metabolic disorders. (4) We will investigate the capacity of sKLB to sensitize endogenous or exogenous FGF21 and thereby elicit metabolic benefits in diet-induced obese mice, which may identify sKLB-based therapeutics and help develop novel approach to overcome FGF21 resistance and enhance therapeutic efficacy of FGF21.

Dr L Geng, Department of Medicine

Dr. Peter Geng, State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, School of Clinical Medicine.

My research team aims to decipher the molecular mechanisms and novel functions of FGF21 and β-Klotho. We are looking for talented MPhil and PhD students.

Biography
Lab Homepage
ORCID
llgeng@hku.hk

For more information or to express interest for this project, please email the supervisor or the specified contact point in the project description.  Interested candidates are advised to enclose with your email:

1. your CV,
2. a brief description of your research interest and experience, and
3. two reference letters (not required for HKUMed UG students seeking MRes[Med]/URIS projects).

Information on the research programme, funding support and admission documentations could be referenced online at the Research Postgraduate Admissions website. General admission enquiries should be directed to rpgmed@hku.hk.

HKUMed MBBS students interested in the Master of Research in Medicine (MRes[Med]) programme may visit the programme website for more information.  

HKUMed UG students interested in the Undergraduate Research Internship Scheme (URIS) may visit the scheme’s website for more information.