The syndrome of resistance to thyroid hormone is characterized by elevated thyroid hormone levels and inappropriate TSH secretion due in almost all cases to point mutations in the TR-b locus. Studies of these naturally occurring TR mutations in vitro have yielded useful insights into the syndrome of RTH. Unfortunately, the generalizability of these studies to the patient's disorder is not always clear and because of their artificial nature may not always be secure. Confounding these issues are the clinical heterogeneity of RTH in families with the same mutation and the suggestion that at least two distinct varieties of RTH are found in man: generalized RTH (GRTH) and central RTH (CRTH). Recently, a TR knockout model in mice has been described having some features in common with RTH but also displaying some significant differences. This autosomal recessive model is in fact pathophysiologically distinct from the vast majority of patients with RTH where a mutant TR expressed from one TR-beta allele dominantly interferes with gene expression by the remaining normal TRs. A few in vivo models of mutant TR-beta overexpression causing RTH have also been described but unfortunately the level and tissue distribution of mutant TR-beta expression may not reproduce that found in RTH patients. Given these limitations, the investigator's laboratory has begun to develop mouse RTH models by introducing point mutations into the TR-beta locus by homologous recombination. This proposal has three aims directed at understanding whether the ligand-independent activity of the TR in vivo is important in the genesis of RTH and whether the selective form, central RTH (CRTH), is a discrete clinical entity. By providing a genetically homogenous background for study and the ability to extensively analyze gene expression in different tissues, these models (Aim 1 and 2) complement ongoing studies in humans with the RTH syndrome (Aim 3).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK049126-06
Application #
6476216
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
1995-08-01
Project End
2005-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
6
Fiscal Year
2002
Total Cost
$227,374
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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