MOLECULAR BASIS OF THYROID HORMONE ACTION

Project: Research project

Description

The broad, long term objectives of this research proposal are to gain
further knowledge on the mechanisms of thyroid hormone action and to
improve our ability to diagnose and treat a group of conditions known as
syndromes of generalized resistance to thyroid hormone (GRTH). In order
to achieve these goals, I plan to study GRTH at the molecular level since
most of, if not all, such patients are likely to have inherited defective
thyroid hormone receptors. I have the largest collection of DNA,
fibroblasts and available patients with GRTH making my ability to execute
this project unique. Recently developed methods for the clinical diagnosis of these syndromes
as well as the recent identification of the genes expressing thyroid
hormone receptor proteins, allow the achievement of these objectives
through the detailed study of these errors of nature. Aim 1 will
determine the prevalence of GRTH in ADHD. Patients suspected with the
diagnosis of GRTH are: (a) referred to our clinic or (b) hopefully
identified through a neonatal screening program with the state of
Illinois; or (c) by screening children with the attention
deficit/hyperactive disorder (ADHD), a condition suspected of having a
high incidence of GRTH. These patients are then admitted to the Clinical
Research Center (CRC) to confirm the diagnosis. Aim 2 will assess the use
of T3 in treatment of children with ADHD and GRTH. DNA from patients with
clinically confirmed GRTH will be screened for abnormalities in the genes
coding for the human thyroid hormone receptors (hTR). The physiological
significance of the identified mutant hTR will be determined.
Transcription and translation of the mutant gene will be done to allow
assessment of the functional domains of the encoded molecules, namely,
their thyroid hormone and DNA binding properties. As there are at least
three different forms of TRs expressed in man (alphal, alpha2, and betal),
the mechanism of action and interaction of these different receptors are
unknown. By defining the mutations in patients with GRTH, this would
contribute to the identification of physiologically relevant thyroid
hormone receptor products and the position of amino acids important for
the proper function of the DNA and hormone-binding domains.
StatusFinished
Effective start/end date7/1/926/30/97

Funding

  • National Institutes of Health: $88,830.00
  • National Institutes of Health: $88,830.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $91,854.00

Fingerprint

Thyroid Hormone Resistance Syndrome
Thyroid Hormones
Thyroid Hormone Receptors
Aptitude
DNA
Neonatal Screening
Hormones
Genes
Research Design
Fibroblasts

ASJC

  • Medicine(all)