Transgenerational Epigenetic Programming of the Thyroid Axis

描述（由申请人提供）：下丘脑-垂体-甲状腺（HPT）轴的内在平衡和反馈机制将甲状腺素（T4）和3，3 '，5-三碘甲状腺原氨酸（T3）的循环和组织水平维持在严格的限度内。这些激素水平反过来又影响着一系列对生物体的健康和适应性至关重要的生理过程。3型脱碘酶（D3），其功能是在组织中使T4和T3脱碘，是甲状腺激素（TH）作用的关键决定因素。D3由小鼠（DIO 3）和人类（DIO 3）中印记的基因编码。在这两个物种中，D3在母胎单位和新生儿中高度表达，在那里它在确保TH浓度中起关键作用。 最适合HPT轴的开发和编程。因此，缺乏D3的小鼠具有改变的血清TH水平，下丘脑、垂体和甲状腺的显著功能障碍，生长受损和其他表型异常。我们从小鼠模型中获得的初步数据强烈表明，TH状态的改变可以通过表观遗传机制诱导后代下丘脑和其他组织中D3表达模式的显着变化。 因此，本提案旨在调查的假设，跨代表观遗传遗传在Dio 3基因座的影响编程的HPT轴和TH代谢和行动的调节整个生命。此外，我们推测，TH本身，从而动物的甲状腺状态，在设置表观遗传标记，部分决定，D3在后代的表达模式中发挥着关键作用。具体地，我们在本文中提出实验以：（1）定义在具有改变的HPT轴的动物的后代中观察到的Dio 3的跨代遗传模式的表型后果;（2）鉴定负责Dio 3跨代遗传的不同模式的表观遗传变化。 (3)确定TH在发育过程中和成年动物中诱导Dio 3基因座上改变的跨代表观遗传遗传中的作用。 值得注意的是，这种遗传过程可能代表了一种新的跨代机制，为HPT轴提供了额外程度的可塑性，以适应稳态挑战。此外，鉴于D3在调节TH的细胞内水平中的重要性，特别是在发育和成年大脑中，新的范例意味着TH的作用的额外的、可遗传的成分，其可能影响心理健康或可想象地易患代谢或生殖功能障碍。

DESCRIPTION (provided by applicant): Intrinsic to the hypothalamic-pituitary-thyroid (HPT) axis are homeostatic and feedback mechanisms that maintain circulating and tissue levels of thyroxine (T4) and 3,3',5-triiodothyronine (T3) within strict limits. These hormone levels in turn influence a host of physiological processes critical to the health and adaptability of the organism. The type 3 deiodinase (D3), which functions to inactivate T4 and T3 in tissues, is a critical determinant of thyroid hormone (TH) action. The D3 is coded by a gene that is imprinted in mice (Dio3) and humans (DIO3). In both species, the D3 is highly expressed in the maternal-fetal unit and in the neonate, where it plays a critical role in ensuring that concentrations of TH are optimal for development and for programming of the HPT axis. Thus, mice deficient in D3 have altered serum TH levels, marked dysfunction of the hypothalamus, pituitary and thyroid glands, impaired growth and other phenotypic abnormalities. Our preliminary data derived from mouse models strongly suggest that alterations in TH status, can, through epigenetic mechanisms, induce marked changes in the expression patterns of the D3 in the hypothalamus and other tissues in subsequent generations of offspring. Thus, this proposal seeks to investigate the hypothesis that transgenerational epigenetic inheritance at the Dio3 locus influences the programming of the HPT axis and the regulation of TH metabolism and action throughout life. Furthermore, we speculate that TH itself, and thus the thyroid status of the animal, plays a key role in setting the epigenetic marks that determine, in part, D3 expression patterns in subsequent generations. Specifically, we propose herein experiments to: (1) Define the phenotypic consequences of the transgenerational inheritance patterns of the Dio3 observed in the descendants of an animal with an altered HPT axis; (2) Identify the epigenetic changes responsible for the varied patterns of Dio3 transgenerational inheritance. (3) Determine the role of TH in the induction of altered transgenerational epigenetic inheritance at the Dio3 locus during development and in adult animals. Notably, this heritable process may represent a novel transgenerational mechanism that provides the HPT axis with an additional degree of plasticity to adapt to homeostatic challenges. In addition, given the importance of the D3 in modulating the intracellular levels of TH, particularly in the developing and adult brain, ths new paradigm implies an additional, heritable component to the action of TH that may impact mental health or conceivably predispose to metabolic or reproductive dysfunction.