Thyroid Hormone Nuclear Receptors in Health and Disease

健康和疾病中的甲状腺激素核受体

基本信息

批准号：
10925966
负责人：
SHEUE-YANN CHENG
金额：
$ 93万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10925966
关键词：
Address Anemia Apoptosis Atrophic Attention deficit hyperactivity disorder Attenuated Binding Biological Biological Assay Biology Bone Development Calmodulin Caveolae Clinical Colon Communication Complex Constipation Defect Development Disease Electrolytes Epithelial Cells Exhibits Feces Female Fibrosis Gap Junctions Gene Expression Gene Expression Regulation Genes Genomics Gland Growth Health Histologic Homeostasis Human Infertility Interstitial Cell of Cajal Laboratories Learning Lymphocyte Function Maintenance Mediating Metabolic Molecular Morphology Mus Muscle Cells Muscle Fibers Mutant Strains Mice Mutation Myosin Light Chain Kinase Myosin Light Chains Nuclear Nuclear Hormone Receptors Patients Phosphorylation Proliferating Protein Isoforms Proto-Oncogene Protein c-kit Publishing Rectum Regulation Reporting Reproduction Research Resistance Role Serum Signal Transduction Smooth Muscle Symptoms THRA gene THRB gene Thyroid Gland Thyroid Hormone Receptor Thyroid Hormone Receptor Gene Thyroid Hormones Thyroid hormone receptor alpha Thyrotropin Time Tissues Transcriptional Regulation Transmission Electron Microscopy Uterus Water Western Blotting fluorescence imaging genetic corepressor hearing impairment hormone response element human disease in vivo insight lucifer yellow mouse model mutant overexpression recruit rectal small molecule transcriptome sequencing

项目摘要

1.TRalpha1 mutants cause morphological and functional defects in mouse model of RTHalpha (Thra1PV/+ mice): We used histopathological analysis, confocal fluorescence imaging, transmission electron microscopy (TEM), and gene expression profiles to comprehensively analyze the colonic abnormalities of Thra1PV/+ mouse. We found a significant increase in colonic transit time and decrease stool water content in Thra1PV/+ mouse, mimicking constipation as found in patients. TEM analysis revealed shorter muscle fibers with wider gap junctions between muscle cells, fewer caveolae, and hypoplastic interstitial cells of Cajal (ICC) in the rectal smooth muscles of Thra1PV/+ mice. These abnormal histological manifestations suggested defective intercellular transfer of small molecules, electrolytes, and signals for communication among muscles cells, validated by Lucifer Yellow transferring assays. Expression of key smooth muscle contractility regulators, such as calmodulin, myosin light-chain kinase, and phosphorylated myosin light chain, was markedly lower, and c-KIT signaling in ICC was attenuated, resulting in decreased contractility of the rectal smooth muscles of Thra1PV/+ mice. Collectively, these abnormal histopathological alterations and diminished contractility regulators led to the constipation exhibited in patients. This is the first demonstration that TRalpha mutants could act to cause abnormal rectum smooth muscle organization, defects in intercellular exchange of small molecules, and decreased expression of contractility regulators to weaken the contractility of rectal smooth muscles. These findings provide new insights into the molecular basis underlying constipation found in RTHalpha patients. These findings have been published in Thyroid (Kim et.al., 2023). 2.Defining the role of TRalpha mutants in uterus functions. Using Thra1PV/+ mice, we found degenerated uterus with fibrosis in the mutant mice. The mutant uterus was atrophied with decreased proliferation, increased apoptosis and reduction in the number of glands. RNA-seq analysis of the uterus showed major alterations in lymphocyte functions and signaling. RNA-seq analysis revealed IL-33 was highly elevated, subsequently validated by RT/qPCR and western blot analysis. Immunohistochemical analysis showed that IL-33 was highly over-expressed in the epithelial cells. The findings that TRalpha mutants could cause degenerated uterus has broadened the scope of the biological impact of mutant actions. Elucidation of how TRalpha mutants cause uterus abnormalities will pave the way for further understanding of the important role of TRalpha in female reproduction biology.

1.曲pha1突变体在RTHALPHA的小鼠模型（Thra1pv/+小鼠）中引起形态和功能缺陷：我们使用组织病理学分析，共焦荧光成像，透射电子显微镜（TEM）和基因表达曲线来全面分析Thra1pv/+鼠标的结肠异常。我们发现结肠过渡时间显着增加，并减少thra1pv/+小鼠中的粪便水含量，模仿患者中的便秘。 TEM分析表明，在Thra1pv/+小鼠的直肠平滑肌中，肌肉细胞，较少的小窝和肌间间质细胞之间的肌肉纤维短，肌肉细胞之间的间隙较大。这些异常的组织学表现表明，小分子，电解质和信号的细胞间转移有缺陷，可通过肌肉细胞之间的通信，并通过路西法黄色转移测定法验证。关键平滑肌肉收缩率调节剂的表达，例如钙调蛋白，肌球蛋白轻链激酶和磷酸化的肌球蛋白轻链的表达明显较低，ICC中的C-KIT信号传导受到衰减，导致Thra1pv/+小鼠的直肠平滑肌的收缩性降低。总的来说，这些异常的组织病理学改变和收缩性调节剂减少导致患者中的便秘。这是第一个证明Tralpha突变体可以引起直肠平滑肌组织异常，小分子的细胞间交换中的缺陷以及降低收缩力调节剂的表达以削弱直肠平滑肌的收缩力。这些发现为RTHALPHA患者发现的分子基础便秘提供了新的见解。这些发现已发表在甲状腺（Kim等，2023）中。 2.指定曲talpha突变体在子宫功能中的作用。使用thra1pv/+小鼠，我们在突变小鼠中发现了纤维化的变性子宫。突变子宫因增殖减少，凋亡增加和腺体数量减少而萎缩。子宫的RNA-seq分析显示淋巴细胞功能和信号传导的重大改变。 RNA-seq分析表明，IL-33高度升高，随后通过RT/QPCR和Western印迹分析验证。免疫组织化学分析表明，IL-33在上皮细胞中高表达。 Tralpha突变体可能导致子宫变性的发现扩大了突变作用的生物学影响范围。阐明Tralpha突变体如何引起子宫异常将为进一步理解Tralpha在女性繁殖生物学中的重要作用铺平道路。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Year in Basic Thyroidology.

基础甲状腺学年。

DOI：
10.1089/thy.2019.0768
发表时间：
2020
期刊：
Thyroid : official journal of the American Thyroid Association
影响因子：
0
作者：
Cheng,Sheue-Yann
通讯作者：
Cheng,Sheue-Yann

NCOR1 modulates erythroid disorders caused by mutations of thyroid hormone receptor α1.

NCOR1 调节由甲状腺激素受体α1 突变引起的红细胞疾病。

DOI：
10.1038/s41598-017-18409-4
发表时间：
2017
期刊：
Scientific reports
影响因子：
4.6
作者：
Han,ChoRong;Park,Sunmi;Cheng,Sheue-Yann
通讯作者：
Cheng,Sheue-Yann

VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis.

DOI：
10.15252/emmm.201607341
发表时间：
2017-06
期刊：
EMBO molecular medicine
影响因子：
11.1
作者：
Jang JY;Choi SY;Park I;Park DY;Choe K;Kim P;Kim YK;Lee BJ;Hirashima M;Kubota Y;Park JW;Cheng SY;Nagy A;Park YJ;Alitalo K;Shong M;Koh GY
通讯作者：
Koh GY

Antitumor Responses Stimulated by Dendritic Cells Are Improved by Triiodothyronine Binding to the Thyroid Hormone Receptor β.

DOI：
10.1158/0008-5472.can-14-1875
发表时间：
2015-04-01
期刊：
Cancer research
影响因子：
11.2
作者：
Alamino VA;Mascanfroni ID;Montesinos MM;Gigena N;Donadio AC;Blidner AG;Milotich SI;Cheng SY;Masini-Repiso AM;Rabinovich GA;Pellizas CG
通讯作者：
Pellizas CG

Regeneration of thyroid follicles from primordial cells in a murine thyroidectomized model.

DOI：
10.1038/labinvest.2016.158
发表时间：
2017-04
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
0
作者：
Lee J;Yi S;Chang JY;Kang YE;Kim HJ;Park KC;Yang KJ;Sul HJ;Kim JO;Yi HS;Zhu X;Cheng SY;Shong M
通讯作者：
Shong M