THYROTROPIN AND ITS RECEPTOR

  • Morris III, John Columbus, (PI)

Project: Research project

Project Details

Description

Although the primary structure of human TSH as well as the structurally
similar gonadotropins LH, FSH, and hCG, has been determined, the three
dimensional structure of the hormone and the details of its
structure-function relationships remain unknown. Current evidence
suggests that several hormone sites are involved in the interaction of
TSH with its receptor and that the sites involve both the TSH specific
beta-subunit as well as the alpha-subunit that is common to all four
hormones. Our recent studies, using a synthetic peptide approach,
identified two regions within the common alpha-subunit and four regions
of beta-TSH that possess binding activity for TSH receptors. The
synthetic peptides representing these sequences were not hormone
agonists, but proved to be antagonists of the intact hormones in bioassay
and also inhibited the bioactivity of the thyroid stimulating
immunoglobulins (TSI) that are the cause of the hyperthyroidism observed
in patients with Graves' disease. In the current application I propose:
1) to study the structure-function relationships of the hTSH
alpha-subunit and to identify further the specific residues of the
subunit that thyroid specific binding and perhaps bioactivity using a
synthetic peptide strategy; 2) to develop specific inhibitors of TSH by
substitution, deletion, and/or chemical modification of the above
identified active amino acid residues; 3) to use a similar synthetic
peptide approach in the study of the recently cloned human TSH receptor
(hTSHr) in order to identify the specific regions of the receptor that
are involved in hormone binding; and 4) to identify the epitope for the
auto-antibodies directed against the hTSHr found in patients with Graves'
disease using the synthetic receptor peptides generated for the above aim
(3). Both the development of inhibitors of TSH, and the identification
of the auto-epitope of the receptor by the synthetic peptide should be
considered important first steps in the direction of specific immune
therapy of autoimmune thyroid disease.
StatusFinished
Effective start/end date6/1/915/31/96

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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