Human xenosensor CAR as novel target for treatment of metabolic disorders.

Collaborative Research Grants Program 2020-2022

The world-wide prevalence of type 2 diabetes mellitus (T2D) shows an increasing trend with estimated doubling of affected population by 2030. Together with other metabolic disorders such as visceral obesity, dyslipidemias and hypertension, T2D significantly increases the long-term risk for serious complications. This is also valid
for the Kazakh society where according to WHO cardiovascular diseases and diabetes are #1 causes of deaths. From societal and economic point of view, the treatment of T2D patients puts an enormous burden on the national healthcare systems and represents one of the highest care costs. Whilst it is without dispute that many remedies are already available for treatments they still lack the precise pathway targeting and employ potential hazardous side effects.
The current multidisciplinary proposal that combines structural bioinformatics and biology, molecular and cellular biology, nutrigenomics and immunology using both established and state of the art methods aims to:

i) find and characterize hCAR-selective ligands by using high-quality in silico and molecular biology techniques together with chemical design and synthesis,

ii) determine specific, ligand-elicited interactions of hCAR with nuclear receptor co-regulators important in energy metabolism,

iii) assess the gene-selective activation of hCAR target genes by measuring the expression and functionality of relevant genes in human liver cell models,

iv) dissect the role of hCAR in glucose and lipid homeostasis in humans by using humanized mice,

v) assess the potential of the ligands for further development of treatment options for metabolic disorders.