Nuclear receptors and human disease. (360G-Wellcome-080237_Z_06_Z)
Many drugs are targeted at nuclear receptors and our aim is to investigate their role in human disease. Wellcome Trust support (1990-2006) has enabled us to identify and study the largest worldwide cohort (~200 families) with Resistance to Thyroid Hormone (RTH) and thyroid hormone receptor beta (TRbeta) mutations or insulin resistance with defects in peroxisome proliferator-activated receptor gamma (PPARgamma). Key future research goals are to: identify & functionally characterise novel genetic defects in human TR & PPARgamma signalling; characterise their phenotype to elucidate pathophysiological mechanisms; study defective receptor-containing human cells/tissues ex vivo. As well as TRbeta mutations, we will seek novel genetic defects mediating RTH and a human homologue of murine TRalpha resistance. We will investigate phenotypes of disordered energy expenditure & appetite, lipid and glucose homeostasis in RTH and use gene expression profiling to investigate pathogenic mechanisms and responses to treatment. We will identify novel PPARgamma gene defects in human metabolic phenotypes and elucidate molecular mechanisms by which germline or somatic (Pax8-PPARgamma) dominant negative forms of PPARgamma interfere with receptor function. We will investigate the metabolic phenotype and its treatment in vivo, and consequences of defective PPARgamma signalling in human primary cells ex vivo.
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Grant Details
Amount Awarded | 955795 |
Applicant Surname | Chatterjee |
Approval Committee | Physiological Sciences Funding Committee |
Award Date | 2006-07-11T00:00:00+00:00 |
Financial Year | 2005/06 |
Grant Programme: Title | Programme Grant |
Internal ID | 080237/Z/06/Z |
Lead Applicant | Prof Krishna Chatterjee |
Other Applicant(s) | Dr M Gurnell |
Partnership Value | 955795 |
Planned Dates: End Date | 2011-07-31T00:00:00+00:00 |
Planned Dates: Start Date | 2006-08-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | East of England |