Central Control of Cardiovascular Function and Energy Expenditure by Thyroid Hormone

甲状腺激素对心血管功能和能量消耗的中枢控制

• 批准号: 258199564
• 负责人: Professor Dr. Jens Mittag
• 金额: --
• 依托单位: Zentrum für Gehirn, Hormone und Verhalten (CBBM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/258199564?language=en
• 关键词: Central; Control; Cardiovascular; Function; Energy

Thyroid hormone is important for brain development and function, modulating behavior as well as the central control of cardiovascular properties and energy homeostasis. However, the underlying cellular and molecular mechanisms are not completely understood. The project of the first funding period aimed to exploit the importance of thyroid hormone and its receptor TRa1 in the central nervous system to obtain a better understanding of the autonomic control of cardiovascular and metabolic functions. Our studies revealed that maternal TRa1 signaling is required for correct fetal programming of cannabinoid receptor 1 expression in the ventromedial hypothalamus of the male wildtype offspring, which regulates their metabolic and locomotor activity. In the second funding period we now aim to study the role of maternal TRb signaling and hyperthyroidism for wildtype offspring. Our preliminary data indicate severe alterations in the cardiovascular and thermoregulatory regulation without alterations in thyroid hormone economy. By dissecting the peripheral and central alterations in these offspring of hyperthyroid mothers using state-of-the-art radiotelemetry and metabolic profiling, we aim to understand more about the central control of cardiovascular functions and energy expenditure.In the second part of the project, we analyzed the role of thyroid hormone for a population of hypothalamic parvalbumin neurons that control heart rate and blood pressure. Using a combination of TRa1 and TRb mutant mice as well as mothers with high thyroid hormone levels during pregnancy, we revealed that both TR isoforms are crucial for the development of these neurons: unliganded TRb seems required for maintaining the proliferation of the precursors cells until E12, whereas liganded TRa1 is necessary for the differentiation after E12 until birth. In the second funding period we now want to build on these findings and treat pregnant females from conception to E12 as well as from E12 to birth with thyroid hormone and analyze the consequences for hypothalamic parvalbumin neuron development as well as cardiovascular function in the offspring. Moreover, using stereotaxic injection of adeno-associated virus vectors, we aim to express dominant-negative and constitutively active thyroid hormone receptors specifically in these neurons to elucidate the role of thyroid hormone signaling for these cells in the adult animal. Our results will contribute to a better understanding of the role of thyroid hormone in the mother as well as the adult offspring for the central control of autonomic functions such as heart rate, blood pressure and exergy expenditure. Moreover, they can reveal previously unknown epigenetic risk factors for cardiovascular disease and obesity.

甲状腺激素对大脑发育和功能、调节行为以及心血管特性和能量稳态的中枢控制很重要。然而，潜在的细胞和分子机制尚未完全理解。第一个资助期的项目旨在利用甲状腺激素及其受体TRa1在中枢神经系统中的重要性，以更好地了解心血管和代谢功能的自主控制。我们的研究表明，母体TRa1信号传导是需要正确的胎儿编程大麻素受体1的表达在腹内侧下丘脑的男性野生型后代，调节他们的代谢和运动活动。在第二个资助期，我们现在的目标是研究母体TRb信号传导和甲状腺功能亢进症对野生型后代的作用。我们的初步数据表明，严重的心血管和体温调节的变化，而甲状腺激素经济的变化。通过使用最先进的无线电遥测和代谢分析来剖析这些甲状腺功能亢进母亲的后代的外周和中枢变化，我们的目标是更多地了解心血管功能和能量消耗的中枢控制。在该项目的第二部分中，我们分析了甲状腺激素对控制心率和血压的下丘脑小清蛋白神经元群体的作用。使用TRa1和TRb突变小鼠以及怀孕期间甲状腺激素水平高的母亲的组合，我们发现两种TR亚型对这些神经元的发育至关重要：未配体化的TRb似乎需要维持前体细胞的增殖直到E12，而配体化的TRa1是E12之后直到出生的分化所必需的。在第二个资助期，我们现在希望以这些发现为基础，从怀孕到E12以及从E12到出生用甲状腺激素治疗怀孕女性，并分析下丘脑小清蛋白神经元发育以及后代心血管功能的后果。此外，使用腺相关病毒载体的立体定位注射，我们的目标是表达显性负性和组成型活性甲状腺激素受体，特别是在这些神经元中阐明甲状腺激素信号传导的作用，这些细胞在成年动物。我们的研究结果将有助于更好地了解甲状腺激素在母亲以及成年后代的自主神经功能，如心率，血压和火用支出的中央控制的作用。此外，它们可以揭示心血管疾病和肥胖症的先前未知的表观遗传风险因素。