Recent Developments And Future Challenges In Thyroidology
Recent Developments and FutureChallenges in ThyroidologyBasic ReviewCHRISTINE SPITZWEG, MDDepartment of Internal Medicine IV – Campus GrosshadernUniversity Hospital of Munich, Ludwig-Maximilians-UniversityMunich, Germany88th Annual Meeting of the American Thyroid Association , October 3-7, 2018, Washington, DC
DisclosuresNothing to disclose
Thyroid hormone & AgingThyroid hormone & Food IntakeThyroid cancerGraham WilliamsJim FaginHeike HeuerTony HollenbergTony BiancoPilar SantistebanBryan HaugenRebecca SchweppeNancy CarrascoSissy JhiangKeith BibleStefan GrebeThe sodiumiodide symporterNISNon-classical thyroid hormone actionNovel thyroid hormone targets
Thyroid hormone & AgingThyroid hormone & Food Intake
Redman LM, et al., Cell Metabolism 2018; 27:805-815
Thyroid hormone &Caloric Restriction2 year calorie restriction trial: Healthy non-obese humans, CR n 34, controls n 19 Calorie restriction is a dietaryintervention with potential benefits forhealthspan improvement and lifespanextension Mechanisms? Observational studies of human aginghave shown higher mass-adjustedmetabolic rate (24h energyexpenditure or resting energyexpenditure) is associated withdisease burden and shorter life spanSustained metabolic adaptationRedman LM, et al., Cell Metabolism 2018; 27:805-815
Thyroid hormone &Caloric RestrictionLeptinyear 1Weight loss phaseT4year 2 Reduction in thyroid axisactivity is a hallmark feature ofthe hypometabolic state withweight loss Drivers for maintainingmetabolic adaptation or aconsequence? Growing evidence thatmechanisms of CR underlyingincreased life span worksignificantly throughmodulation of thyroid axisWeight loss maintenanceRedman LM, et al., Cell Metabolism 2018; 27:805-815
Hine C, et al., Cell Metabolism 2017; 25:1320-1333
Thyroid hormone &hepatic H2S production Decreased thyroid hormone andgrowth hormone signaling areassociated with longevity andmetabolic fitness Possible overlapping mechanismswith those of dietary restrictionresulting in downregulation ofTH/GH axis Potential mediator is the longevityassociated gas H2S, which isincreased upon dietary restrictionHine C, et al., Cell Metabolism 2017; 25:1320-1333
Thyroid hormone &hepatic H2S productionPleiotropic beneficial effects ofH2SResistance tohypoxiaNeuroprotectionModulation ofinflammationAngiogenesis incardiovascular systemExtension oflongevityHine C, et al., Cell Metabolism 2017; 25:1320-1333
Thyroid hormone &hepatic H2S productionTSH and GH deficiency/inhibition promote hepatic H2S production in vivoHine C, et al., Cell Metabolism 2017; 25:1320-1333
Thyroid hormone &hepatic H2S productionHypothyroidism increases / thyroid hormone represses hepatic H2S production in vivovia TRb1Hine C, et al., Cell Metabolism 2017; 25:1320-1333
Thyroid hormone &hepatic H2S productionTH / GH are negative regulators of H2S productionTH / GH signaling could be the link between DR and H2S productionH2S is involved in negative regulation of TH / GH signaling, key longevity associatedhormones potential mechanism of H2S action and mediator of its beneficial effectsHine C, et al., Cell Metabolism 2017; 25:1320-1333
Thyroid hormone & keylongevity associated hormoneRotterdam StudyBano A, et al., JAMA Intern Med 2017; 11:1650-1657
Hameed S, et al., Cell Reports 2017; 19:2202-2209
TRb in VMH & Regulationof food intake Improved understanding ofthe mechanisms thatregulate appetite and bodyweightdesign of antiobesity therapies The TR-beta isoform (TRb)is expressed in theventromedial hypothalamus(VMH)- a brain areaimportant for control ofenergy homeostasisHameed S, et al., Cell Reports 2017; 19:2202-2209
TRb in VMH & Regulationof food intakeTRb knockdown in the VMH results in a phenotype of hyperphagia comparable to some of themost extreme forms of monogenic obesityHypothalamic TRb major physiological regulator of energy homeostasisHameed S, et al., Cell Reports 2017; 19:2202-2209
Non-classical thyroid hormone actionNovel thyroid hormone targets
Noncanonical TRsignalingEstablishment of- TRaGS and TRbGS mice with loss of canonical TR signaling- TRb147F with abolished non-canonical TRb signalingHönes GS, et al., PNAS 2017; 114:E11323-E11332
Noncanonical TRbsignalingBlood glucoseBody temperatureSerum and liver triglyceride concentrationOxygen consumptionHönes GS, et al., PNAS 2017; 114:E11323-E11332
Noncanonical TRasignalingBasal heart rateNoncanonical TR signaling contributes significantly to physiologic actions of THNoncanonical TR signaling predominantly regulates energy homeostasisProfound implications for the role of TRs in metabolism and physiologyExplain the pathophysiology in diseases caused by the various TR mutationsParadigm shift for TH actionHönes GS, et al., PNAS 2017; 114:E11323-E11332
Thyroid hormone &lung fibrosisYu, G et al., Nature Med 2018; 24:39-49
Thyroid hormone &lung fibrosisDIO2 expression and activity in IPF patient lungsLung Genomic Research Consortium data setCTRLIPFYu, G et al., Nature Med 2018; 24:39-49
Thyroid hormone &lung fibrosisDIO2 expression and activity in IPF mouse model (bleomycin model of lung fibrosis)Yu, G et al., Nature Med 2018; 24:39-49
Thyroid hormone &lung fibrosisAerosolized T3 treatment in IPF mouse modelsNew role of thyroid hormone as potential therapeutic agent in IPF T3 blunts lung fibrosis T3 reverses bleomycin-inducedmitochondrial changes T3 suppresses mitochondriaregulated apoptosis Upregul. of DIO2 effort to boostlocal conversion of T4 to T3Yu, G et al., Nature Med 2018; 24:39-49
Thyroid cancer
Genetic profiling ofadvanced DTC and ATCPozdeyev N, et al., Clin Cancer Res 2018; 24:3059-3068
Genetic profiling ofadvanced DTC and ATCPTCPozdeyev N, et al., Clin Cancer Res 2018; 24:3059-3068
FTCGenetic profiling ofadvanced DTC and ATCPediatric PTCPozdeyev N, et al., Clin Cancer Res 2018; 24:3059-3068HCTC
Genetic profiling ofadvanced DTC and ATCATCPozdeyev N, et al., Clin Cancer Res 2018; 24:3059-3068
Genetic profiling ofadvanced DTC and ATCPozdeyev N, et al., Clin Cancer Res 2018; 24:3059-3068
Genetic profiling ofadvanced Hurthle cell cancerGopal RK, et al., Cancer Cell 2018; 34:242-255Ganly I, et al., Cancer Cell 2018; 34:256-270
Genetic profiling of Hurthlecell cancerGanly I, et al., Cancer Cell 2018; 34:256-270Gopal RK, et al., Cancer Cell 2018; 34:242-255
Resistance to BRAFinhibitors in ATCKnauf JA, et al., J Clin Invest 2018; 128:4086-4097
Resistance to BRAFinhibition in ATCKnauf JA, et al., J Clin Invest 2018; 128:4086-4097
Resistance to BRAFinhibition in ATCResistance to BRAF inhibition involves activation ofHGF/Met signaling that can be targeted by MET inhibitorsKnauf JA, et al., J Clin Invest 2018; 128:4086-4097
miR-146b – a novel target forthyroid cancer therapy?Riesco-Eizaguirre G, et al., Cancer Res 2015; 75:4119-4130Ramirez-Moya J, et al., Oncogene 2018; 37:3369-3383
miR-146b – a novel target forthyroid cancer therapy?Riesco-Eizaguirre G, et al., Cancer Res 2015; 75:4119-4130
miR-146b – a novel target forthyroid cancer therapy?Modulation of the PI3K signaling by miR-146b via PTEN silencingTherapeutic efficacy of the hsa-miR-146b-5pmir-Vana miRNA inhibitorRamirez-Moya J, et al., Oncogene 2018; 37:3369-3383
Liu R, et al., Nature Commun 2018; 9:579-592
Oncogene duetmutant TERT & BRAF V600E Oncogene duet of BRAF V600E and TERT promoter mutations is a fundamental geneticbackground cooperatively driving progression/aggressiveness of cancers, i.e. PTCMolecular mechanism for synergistic oncogenic effect?Liu R, et al., Nature Commun 2018; 9:579-592
Oncogene duetmutant TERT & BRAF V600EUpregulation of GABPB by BRAF V600EGABPB complex a known activatorof mut TERT promoterFOS transcription factor of the GABPB geneBRAF/MAPK-induced FOS activation, a transcription factor activating GABPB promoter,a known activator of mut TERT promoter plays a key role in bridging the 2 oncogenescooperatively driving oncogenesisLiu R, et al., Nature Commun 2018; 9:579-592
The sodium iodide symporterNIS497485Extrac ellul ar115311 7986III372Intr acell 8VIII26028611340IX411X368641 - Sequence NumbersI - Transmembrane Domains1 - ExM Domains- N-linked glycosylation sites417XI468XII388 4384441210864314522XIII550
NIS knockout mouse modelFerrandino G, et al., Sci Rep 2017; 7:5329-5340
NIS knockout mouse modelStandard chow diet (6 µg I-/g)Ferrandino G, et al., Sci Rep 2017; 7:5329-5340
NIS knockout mouse modelMinimal iodide diet (0.15 µg I-/g)Thyroid hormone is synthesized in NIS KO mice as long as I- supply is sufficient to enter thethyroid most likely by diffusion via non-specific routes driven by a concentration gradientI- gradient (serum/thyroid) is maintained by upregulating genes involved in I- organificationEnhanced oxidative environment in the thyroid (adaptive response)Ferrandino G, et al., Sci Rep 2017; 7:5329-5340
NIS gene therapy inpancreatic cancerSchug C, et al., Mol Cancer Res 2018; in press
NIS gene therapy inpancreatic cancerPtf1a /Cre; Kras /LSL-G12D;p53LoxP/LoxP (CKP)Schug C, et al., Mol Cancer Res 2018; in press
Special ThanksThyroid hormone & AgingThyroid hormone & Food IntakeThyroid cancerGraham WilliamsJim FaginHeike HeuerTony HollenbergTony BiancoPilar SantistebanBryan HaugenRebecca SchweppeNancy CarrascoSissy JhiangKeith BibleStefan GrebeThe sodiumiodide symporterNISNon-classical thyroid hormone actionNovel thyroid hormone targets
Sissy Jhiang Keith Bible Stefan Grebe. Thyroid hormone & Aging Thyroid hormone & Food Intake. Redman LM, et al., Cell Metabolism 2018; 27:805-815. Thyroid hormone & Caloric Restriction Sustained metabolic adaptation Calorie restriction is a dietary intervention with potential benefits for
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