American Thyroid Association Corporate Leadership Council May 14, 2010 Minneapolis, Minnesota.

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  • American Thyroid Association Corporate Leadership Council May 14, 2010 Minneapolis, Minnesota

  • "..I have seen societies come and go..I recognize a harmonious and understanding attitude between those who are interested in almost pure science, bordering on its relation to clinical medicine, and the rest of us...Even if we often do not possess the fundamental training and experience to understand them fully, we listened with profit to these scientific papers that have been presented to us..."

  • 1. Mayo Clinic, Rochester, Minn.3. Johns Hopkins Hospital, Baltimore7. Brigham and Women's Hospital, Boston10. Hospital of the University of Pennsylvania14. University of Chicago16. Washington Hospital Center17. University of Michigan19. Cedars-Sinai Hospital23. Baystate Medical Center24. Methodist Hospital

  • National Academy of Sciences-1Institute of Medicine-2Medical School Deans and Associate Deans-Northwestern, UCLA, Georgetown, Harvard, former-Yale, Univ of Alabama, UC San Diego Scientific Director NIDDK (Natl Institutes of Health)Department Chairs; Medicine, Pediatrics, Surgery, ENT, Genetics-12University/Major Medical Center Division Chiefs-20NIH Molecular and Cellular Endocrinology Study Section-3 of 15 regular members, current chair and 2 past chairs

  • ConditionReported Prevalence in Adult Population (%)Hypothyroidism2Mild (subclinical) hypothyroidism5-17Hyperthyroidism0.2Mild (subclinical) hyperthyroidism0.1-6

  • Prevalence of Mild Thyroid Failure Across Studies: Women by Decade1. Tunbridge W, et al. Clin Endocrinol. 1977;7:481-493. 2. Canaris G. Arch Intern Med. 2000;160:526-534. 3. Hollowell J. J Clin Endocr Metab. 2002;87:489-499. 051015202530s50s80s% of Women Colorado2 (N=25,862) NHANES3 (N=17,353) Whickham1 (N=2779)Decade of Age

  • http://seer.cancer.gov/cgi-bin/csr/1975_2006

  • Smith, et al., J Clin Oncol 2009

  • Thyroid autoimmunity -prevalent disease, familial, identify triggers, genetic susceptibility, antigen-antibody interactions, antagonists, application to other autoimmune conditions (eg. Type 1 diabetes).Thyroid hormone action -development in mammals and amphibians, tissue specificity, analogs, metabolic regulation, neural development, adult brain function, bone growth and remodeling, crystal structure-function, central regulation of TRH/TSH, environmental toxicants.

  • Thyroid hormone metabolism -developmental role, deiodinase enzyme structure/function/regulation, regulation in tissues (tumors, skeletal muscle, brain), interface with adrenergic system, role in metabolic regulation. Thyroid cancer-mechanism of onset, mechanism of spread, iodine transport and regulation, molecular diagnostics, targeted therapy.Thyroid and the heart-mechanism of action, role in atrial fibrillation and heart failure, therapy for heart failure, vascular action to reduce resistance.

  • Thyroid Clinical-thyroid disease in pregnancy, iodine intake and influence on thyroid function, thyroid and brain development, psychiatric disease, cardiovascular effects, bone effects, thyroid nodule evaluation, impact of mild thyroid disease, epidemiology, thyroid and aging (bone loss, frailty), thyroid function testing, .Related Areas-Sodium/iodide symporter (NIS) regulation in tumors and NIS gene therapy, pharmacological treatment in psychiatric disease, interaction with feeding behavior, sleep, circadian rhythms.

  • Potential Applications of Thyroid Hormone AnalogsBrenta G et al, Nature Clin Pract Endocrin Metab 3:632, 2007Thyroid hormones T4 and T3Thyroid hormone analogsPituitary GlandCardiovascular SystemLiverAll Organ SystemsTSH suppression(negative regulation ofTSH -subunitCardiac OutputHeart Rate (HCN2)Contractility (SERCA2, MHCs)Systemic Vascular Resistance

    Cholesterol Metabolism(SERBP-2 sterol regulatoryelement binding protein-stimulatesLDL-R gene, CYP7A-cholesterol7 hydroxylase-bile acid syn/cholesterolClearance, CETP-cholesterol estertransfer protein)

    Thermogenesis and V02(ATP turnover, muscle mass,facultative thermogenesis)

  • 100%87%DBD Hinge LDBTRb1TRa1N-terminal410461P448HP398Hcofactor interaction interface ActivationThyroid Hormone Receptors and Functional Domains

  • Liu and Brent Trends Endo Metab 2010; 21:166

    SERBP-2 sterol regulatory element binding proteinCYP7A-cholesterol 7 hydroxylaseCETP-cholesterol ester transfer protein

  • Rulon Rawson, MDPresident, American Goiter AssociationPresidential Address, 1956

  • Selective Thyromimetics

  • Baxter and Webb Nature Drug Discovery 8:308, 2009

  • Cable et al Hepatology 49:407, 2009Liver-Activated Thyroid Hormone Receptor AnalogMB07811 is a phosphonate containing derivative of MB07344with high first-pass extraction in the liver and activated byCytochrome P450 3A

  • Cable et al Hepatology 49:407, 2009VehicleMB07811 10mgMB07811 30mg

  • Baxter and Webb Nature Drug Discovery 8:308, 2009

  • Ladenson et al N Engl J Med 2010 362:906

  • Lichtenbelt N Engl J Med 360:1500, 2009LeanHighBATLeanModBATObese2 hoursExposure16CBrown Adipose Tissue in Humans

  • Klein I, Danzi S. Circulation 2007; 116:1725Thyroid Hormone Actions on the Cardiovascular System

  • Goldman et al Circulation 119:3093, 2009End Diastolic DiameterCardiac Index

  • DITPAThyroid Hormone Analogs

  • Thyroid Hormone SynthesisCoupling ReactionsDIT+DIT=T4MIT+DIT=T3NIS-Sodium Iodide Symporter, TPO-thyroid peroxidase, D1/D2-5-deiodinase 1 and 2 Coupling ReactionsMIT+DIT=T3DIT+DIT=T4

  • Kondo, et al., Nat Rev Cancer 2006

  • Neumann et al Endocrinology 149:5945, 2008

  • Neumann et al Endocrinology 149:5945, 2008Low Molecular Weight Compound 52 Antagonizes TSHStimulation of the TSH-Receptor

  • ThyroidSalivary GlandStomachLactating Breast

  • Transactions of the American Goiter Association 1951

  • Xing, et al., J Clin Oncol, 2009

  • Bauer et al J Clin Endocrinol Metab 94:2922, 2009PCC-posterior cingulate cortexACC-anterior cingulate cortex

  • P13, ~ onset of hearingP0, birthP20, weaningDio2 activatingamplify hormoneconceptionThyroid hormone and the senses: the example of hearing

    Multiple genes determine the nature, cell-specificity and timing of the response to T3

    Adequate amounts of thyroid hormone in the circulation are necessary

    The cochlea auto-regulates its hormonal response: Dio2 and Dio3, double control over timing

    Critical period of maturation of auditory function, depends upon T3 Dio3 inactivatinglimit hormoneTR~ E12critical period

  • MCT8-Thyroid Hormone TransporterHierarchy of ligand preference T3>T4>rT3~T2Visser et al Best Prac Res Clin Endo Metab 21:223, 2007Model of the role of astrocytes expressing D2 to convert T4 to T3 and neurons expressing the MCT8 transporter to take up T3.

  • Mutations in the monocarboxylase transporter 8 (MCT8) gene located on X chromosome.Neurologic and thyroid function test abnormalities in males carrying the mutationNeurologic abnormalities include dystonia, developmental delay, and progressing to quadriplegiaInactivating mutations of the MCT8 gene identified

  • Alan-Herndon-Dudley Syndrome-X Linked Mental RetardationSchwartz and Stevenons, Best Prac Res Clin Endo Metab 21:307, 2007

  • DITPAThyroid Hormone Analogs

  • *****The data shown in this slide represents the prevalence rates for mild thyroid failure between studies1-3 for women.Note that by age 50, one out of every 10 women show evidence of mild thyroid failure.Although is is widely believed that the prevalence of thyroid disease is decidedly greater in women than men, clinicians should not lose sight of the high percentage of men that are affected by thyroid gland failures, particularly among older patients.

    ReferencesTunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf). 1977;7:481-493.Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526-534.Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489-499.

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