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

研究甲状腺生理学的新型无创高分辨率体内成像平台

基本信息

批准号：
10042718
负责人：
Joao Pedro Saar Werneck de Castro
金额：
$ 19.19万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-21 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10042718
关键词：
3-Dimensional Adrenergic Agents Architecture Biology Blood Circulation Blood Vessels Blood flow Caliber Cells Cellular Structures Cellular biology Cyclic AMP Data Detection Diet Endocrine Environment Eye Functional disorder General Population Gland Goals Histologic Hormone secretion Human Image In Vitro Incidence Injections Iodine Knowledge Laboratories Malignant Neoplasms Measurement Metabolic Diseases Methods Modification Monitor Mus Organism Outcome Physiological Physiology Plasma Play Property Reporting Research Resolution Risk Factors Role Specimen Stimulus Structure System Technology Testing Thyroglobulin Thyroid Gland Thyroid Hormones Thyrotoxicosis Time Tissues Transgenic Mice Translations Transplantation Vascular Permeabilities Vascularization Visualization anterior chamber base cell growth cholinergic eye chamber imaging platform in vivo in vivo imaging innovation insight iodine deficiency syndrome longitudinal analysis mouse model novel novel strategies response thyroid transplantation tool

项目摘要

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.

项目概要/摘要生物体的所有组织都依赖正常的甲状腺激素水平来正常发育和发挥功能。百万全世界的人患有甲状腺功能障碍 (TD)。一般人群中 TD 的发生率为 4-10% 患有代谢疾病的人的比例要高得多。尽管甲状腺在其中发挥着核心作用人类生理学，我们对甲状腺细胞生物学的大部分了解，甲状腺滤泡细胞生长的控制，脉管系统适应和内分泌相互作用源自组织学评估和体外限制翻译到体内环境的研究。值得注意的是，这些体外设置并没有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，体内由于缺乏研究甲状腺生理学和病理生理学的方法，甲状腺生理学和病理生理学的研究受到阻碍。甲状腺可以通过其自然结构进行评估。我研究的长期目标是了解活体中甲状腺的细胞生物学。当前应用程序的强度依赖于我我在实验室开发的强大技术平台的初步数据。这种新颖的方法允许对小鼠和人类滤泡细胞进行无创实时体内成像。该技术是基于将小鼠和人类甲状腺碎片移植到小鼠眼睛中，血运重建；它可以分析甲状腺移植物大小、血流量和甲状腺移植物的纵向变化血管直径，以及甲状腺血管滤泡单位的三维体内图像。我的假设是将小鼠和人类甲状腺移植到小鼠眼前房类似于甲状腺的正常细胞结构并概括对碘缺乏的反应/适应甲状腺毒症。为了检验我的假设，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和 2) 增益对人和小鼠血管滤泡单位及其细胞成分适应的体内见解缺碘和甲状腺毒症。我将研究移植了小鼠和人类甲状腺标本的小鼠并操纵不同的内分泌刺激。转基因小鼠模型将让我第一次展示体内甲状腺细胞激活的时间。我将通过过度激活甲状腺来挑战该系统实验性缺碘。对甲状腺毒症（甲状腺激素水平升高）的反应也会进行评估。这个创新平台将通过允许可视化来克服主要的技术障碍以及体内甲状腺生物学动态特性的测量。在他们的成功完成后，我的研究将增强我们对脉管系统适应和甲状腺的体内机制的了解滤泡细胞生长。我预测部署这些方法将为对人类甲状腺生理学和甲状腺恶性肿瘤的了解取得进展。