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Endoplasmic Reticulum stress and thyroid cell death

Award Number: R01DK132017
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Endoplasmic Reticulum stress and thyroid cell death - ABSTRACT Efficient generation of the thyroid hormone thyroxine (T4) requires the iodination of thyroglobulin (Tg), which is synthesized in the endoplasmic reticulum (ER) and undergoes folding and trafficking to the thyroid follicle lumen wherein iodination takes place. Endogenous T4 is 100% produced by thyrocytes, and the formation of T4 in Tg has been conserved in evolution for ≥ 500 million years. To date, hundreds of different pathogenic mutations of the TG gene have been found to cause congenital hypothyroidism in humans. Genetic hypothyroidism from homozygous (or compound heterozygous) TG mutation is rare, but the frequency of a single pathogenic TG allele in the human population is very common (≥ 1:200 individuals). All Tg mutants studied to date are misfolded proteins trapped in the ER, causing ER stress. We recently reported that in untreated TG homozygotes, endogenous thyroid hormone synthesis still occurs despite failure of Tg export from the ER. The mechanism involves thyroid epithelial cell death, with extrusion of dead thyrocytes into the lumen of thyroid follicles, leading to the disintegration and iodination of those cells in the follicle lumen. Massive expression of Tg protein in thyrocytes, and the extremely high frequency of heterozygous TG mutations in the population, now leads us to ask whether thyroid epithelial cell death may also be a (heretofore unsuspected) widespread feature across individuals who are simple heterozygotes for mutant TG. This can be easily tested in animal models. Additionally, in homozygous rdw/rdw (Tg-G2298R) rats, thyroid cell death has long been recognized as a factor blocking goiter growth. Remarkably, we now find that in the congenital goiter mouse (cog/cog, Tg-L2263P), there is also widespread thyroid cell death (that is nevertheless outpaced by thyroid growth). In the current proposal, 1) we have engineered a rdw/rdw knockin mouse and will directly compare cell growth and cell death to that seen in cog/cog mice. 2) We will examine thyroid cell death in simple heterozygotes of these two models, which have perfectly normal serum T4 levels but exhibit thyrocyte ER stress. 3) As heterozygous mutant Tg is misfolded in the ER, it may be degraded at least in part by ER-associated protein degradation (ERAD). We find that defective ERAD of Tg leads to a thyroiditis with infiltration of inflammatory cells and follicle involuion. 4) Extrusion of thyrocytes into the follicle lumen may expose non-apical portions of the cell to iodination by surrounding follicular cells as a contributing mechanism of cytotoxicity. To test this, we will examine a TG-KO mouse model in which TSH-stimulated overgrowth (and not ER stress) drives thyrocytes into the follicle lumen, exposing the sensitive basolateral plasma membrane to the oxidative / iodination environment of the lumen, where it may trigger thyroid cell death. In summary, all of the Aims of this proposal will highlight questions of ER stress- dependent and independent mechanisms of thyrocyte death.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $390,000 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/3/2025	NON-COMPETING CONTINUATION	$351,000
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/12/2025	NON-COMPETING CONTINUATION	$39,000
														Subtotal = $390,000

Issue Date FY: 2024 ( Subtotal = $374,400 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/7/2024	NON-COMPETING CONTINUATION	$23,400
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/10/2024	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $374,400

Issue Date FY: 2023 ( Subtotal = $390,000 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/29/2023	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2022 ( Subtotal = $390,000 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/22/2022	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $1,544,400

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Endoplasmic Reticulum stress and thyroid cell death

Award Number: R01DK132017

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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