Thyroid hormone is a critical mediator of fetal development and then essential for normal metabolic and neurologic function during adulthood. Its synthesis by the thyroid is governed by a developmental process that begins during embryogenesis in mammals. An understanding of this process and the steps involved would have profound effects on our understanding of congenital hypothyroidism which occurs in 1/4000 births and additionally on potential cellular therapy for hypothyroidism in humans. Additionally, the development of functional thyroid follicular cells at different stages of development would provide an ideal model system to understand numerous diseases including thyroid cancer and defects in thyroid hormone synthesis. Importantly, we have developed a unique culture system to develop functioning thyroid follicular cells from mouse embryonic stem cells that does not rely on the forced overexpression of transcription factors. Importantly, the signaling pathways involved appear to be conserved in Xenopus and human thyroid development. Thus, we are now in position to mechanistically prove the process and finalize its function in human cells. To accomplish this we propose three Aims. In the first Aim, we will assess the role of two key signaling pathways we have identified in murine follicular cell development to ensure that differentiation program we have developed parallels endogenous thyroid development. In the second Aim, we will leverage our mouse culture system and develop technology to transform human induced pluripotent stem cells into thyroid follicular cells. Finally, in Aim 3 we will use genetic-editing to repair human mutations that cause congenital hypothyroidism and demonstrate that this repair allows for normal thyroid follicular development. Together completion of these Aims will provide key insight into how the thyroid develops and functions and allow for the potential of cellular therapies to treat thyroid disease.

Public Health Relevance

Thyroid hormone (TH) is a critical mediator of fetal development and then essential for normal health during adulthood. Currently, therapy for those with hypothyroidism (either congenital or acquired later in life) is with L-thyroxine and many individuals on therapy do not feel adequately replaced. In this proposal, we put forward experiments designed to develop thyroid hormone secreting follicular cells from mouse embryonic stem cells and human induced pluripotent stem cells. Completion of this work will give us significant insight into the developmental biology of the thyroid and potentially offer a unique and powerful approach to treat hypothyroidism in humans. Furthermore, the development of follicular cells from progenitor cells will give us an ideal model to better understand many disease of the thyroid that affect human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK105029-03
Application #
9380961
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Silva, Corinne M
Project Start
2015-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Hollenberg, Anthony N; Choi, Jinyoung; Serra, Maria et al. (2017) Regenerative therapy for hypothyroidism: Mechanisms and possibilities. Mol Cell Endocrinol 445:35-41
Hawkins, Finn; Kramer, Philipp; Jacob, Anjali et al. (2017) Prospective isolation of NKX2-1-expressing human lung progenitors derived from pluripotent stem cells. J Clin Invest 127:2277-2294
Serra, Maria; Alysandratos, Konstantinos-Dionysios; Hawkins, Finn et al. (2017) Pluripotent stem cell differentiation reveals distinct developmental pathways regulating lung- versus thyroid-lineage specification. Development 144:3879-3893
Mendoza, Arturo; Hollenberg, Anthony N (2017) New insights into thyroid hormone action. Pharmacol Ther 173:135-145