Novel noninvasive high-resolution in vivo imaging platform to study the thyroid gland physiology

项目总结/摘要 生物体的所有组织都依赖于正常的甲状腺激素水平来正常发育和发挥功能。数百万 的人患有甲状腺功能障碍（TD）。TD发病率在一般人群中为4-10%， 在患有代谢疾病的人中要高得多尽管甲状腺在甲状腺疾病中扮演着重要角色， 人类生理学，我们所知道的甲状腺细胞生物学，甲状腺滤泡细胞生长的控制， 血管适应和内分泌相互作用已从组织学评估和体外研究中得出， 限制翻译到体内环境的研究。值得注意的是，这些体外设置不能复制 甲状腺的基本功能单位，特别是三维血管滤泡单位。因此，在体内 甲状腺生理学和病理生理学的研究受到缺乏方法的阻碍， 甲状腺可以在其自然结构中评估。我研究的长期目标是了解 甲状腺的细胞生物学。本申请的强度依赖于我的 我在实验室开发的一个强大的技术平台的初步数据。这种新方法 允许小鼠和人滤泡细胞的非侵入性实时体内成像。该技术基于 将小鼠和人甲状腺片段移植到小鼠眼睛中， 成为血运重建;它允许分析甲状腺移植物大小，血流量和 血管直径，以及甲状腺血管滤泡单位的三维体内图像。我的假设是 移植到小鼠眼前房的小鼠和人类甲状腺类似于 甲状腺的正常细胞结构，并概括了对碘缺乏的反应/适应， 甲状腺毒症为了验证我的假设，我将追求两个具体目标：1）获得独特的体内细胞内 血管-毛囊单位的生理测量及其对生理刺激的反应，以及2） 对人类和小鼠血管滤泡单位及其细胞成分适应的体内见解， 碘缺乏症和甲状腺毒症。我将研究移植了老鼠和人类甲状腺标本的老鼠 操纵不同的内分泌刺激。转基因小鼠模型可以让我第一次展示 体内甲状腺细胞活化时间。我会挑战这个系统通过激活甲状腺 实验性碘缺乏对甲状腺毒症的反应（甲状腺激素水平升高）也会 进行评估。这个创新的平台将克服一个主要的技术障碍， 以及甲状腺生物学在体内的动态特性的测量。在他们成功完成后， 我的研究将提高我们对血管适应和甲状腺功能的体内机制的认识。 滤泡细胞生长我预测，部署这些方法将为以下方面提供前所未有的机会： 在人类甲状腺生理学和甲状腺恶性肿瘤的理解进步。

Project Summary/Abstract All tissues of a living organism rely on normal thyroid hormone levels to develop and function properly. Millions of people world-wide suffer from thyroid dysfunction (TD). TD incidence is 4-10% in the general population and is considerably higher in people with metabolic diseases. Despite the central role that thyroid gland plays in human physiology, most of what we know about thyroid cell biology, control of thyroid follicular cell growth, vasculature adaptation and endocrine interactions has been derived from histological assessments and in vitro studies that limit translation to the in vivo environment. Remarkably, these in vitro set-ups do not replicate the basic functional unit of the thyroid, particularly the three-dimensional angio-follicular unit. Therefore, in vivo studies of thyroid gland physiology and pathophysiology are hindered by the lack of approaches in which the thyroid gland can be assessed in its natural architecture. The long-term goal of my research is to understand the cell biology of the thyroid gland in the living organism. The strength of the present application relies on my preliminary data of a robust technological platform that I developed in my laboratory. This novel approach allows noninvasive real-time in vivo imaging of the mouse and human follicular cell. The technology is based on transplantation of the mouse and human thyroid fragments into the mouse eye, which engrafts and becomes revascularized; it permits the analysis of longitudinal changes in thyroid graft size, blood flow and vessel diameters, with three-dimensional in vivo images of the thyroid angio-follicular unit. My hypothesis is that mouse and human thyroid gland transplanted into the mouse anterior chamber of the eye resembles the normal cellular structure of the thyroid and recapitulate the responses/adaptations to iodine deficiency and thyrotoxicosis. To test my hypothesis, I will pursue two specific aims: 1) obtain unique in vivo intracellular physiological measurements of the angio-follicular unit and its response to physiological stimuli and 2) gain in vivo insights into the adaptation of the human and mouse angio-follicular unit and its cellular components to iodine deficiency and thyrotoxicosis. I will study mice transplanted with mouse and human thyroid specimens and manipulate different endocrine stimuli. Transgenic mouse models will allow me to demonstrate for the first time thyrocytes activation in vivo. I will challenge the system by hyperactivating the thyroid gland with experimental iodine deficiency. The responses to thyrotoxicosis (increased levels of thyroid hormone) will also be assessed. This innovative platform will overcome a major technical roadblock by allowing the visualization and measurement of dynamic properties of the thyroid gland biology in vivo. At their successful completion, my studies will enhance our knowledge of the in vivo mechanisms of vasculature adaptation and thyroid follicular cell growth. I predict that deploying these methods will provide unprecedented opportunities to advance in the understanding of human thyroid physiology and thyroid malignancies.