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The Role of GCM2 in Parathyroid Gland Homeostasis

GCM2 在甲状旁腺稳态中的作用

基本信息

批准号：
8871435
负责人：
MICHAEL ALAN LEVINE
金额：
$ 54.88万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-22 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8871435
关键词：
Ablation Adult Age Alleles Atrophic Bilateral Binding Sites Biochemical Calcium Cataloging Catalogs Cell Death Cell Line Cells Cellular biology ChIP-seq Companions Computer Simulation DNA-Binding Proteins Data Defect Development Developmental Biology Disease of parathyroid glands Embryo Embryonic Development Endoderm Cell Erinaceidae Fourth Pharyngeal Pouch Funding Future Gene Dosage Gene Expression Genes Genetic Transcription Genetically Engineered Mouse Goals Growth Hand Health Homeostasis Human Hybrids Hyperparathyroidism Hyperplasia Hypoparathyroidism Knowledge Lead Life Lobe Location Medical Mission Modeling Molecular Molecular Biology Molecular Genetics Molecular Target Mus Mutate Neuroglia Outcome PTH gene Parathyroid Neoplasms Parathyroid gland Partner in relationship Pathogenesis Pathway interactions Patients Phosphorus Physiology Play Primordium Proteins Public Health Reagent Reporter Repression Research Research Project Grants Role Serum Siblings Signal Transduction Site Tamoxifen Techniques Technology Testing Therapeutic Thymus Gland Time Transcriptional Regulation Transgenic Mice United States National Institutes of Health Work Yeasts base genetic regulatory protein gland development innovation insight loss of function mutation mouse model new therapeutic target novel novel strategies novel therapeutic intervention overexpression postnatal promoter protein function recombinase research study screening smoothened signaling pathway therapeutic target transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): This resubmitted proposal for funding is the result of 2 years of ARRA R01 funding that generated novel data demonstrating a critical role for the parathyroid cell-specific transcription factor Gcm2 (glial cell missing 2) after early embryologica development of the parathyroid glands as well how this protein functions in mature parathyroid glands to control function and survival of parathyroid cells. The long-term goal is use knowledge of the role of Gcm2 to develop novel strategies for medical treatment of patients with hyperparathyroidism. The objective in this application is to identify the extent to which depletion of Gcm2 leads to reduced survival of parathyroid cells in genetically engineered mouse models. The central hypothesis is that expression of Gcm2 in the parathyroid is necessary throughout life to maintain parathyroid cell mass, and that lack of Gcm2 will induce parathyroid cell death. We propose to use mouse models that we have developed to genetically delete the Gcm2 gene conditionally, in a temporally controlled manner, to identify the genes that regulate expression of Gcm2 as well as those that are controlled by Gcm2 action, and to uncover the effect of loss of Gcm2 on mature parathyroid cells. Mice with conditional Gcm2 alleles will also allow us to determine the extent to which ablation of Gcm2 late in life can "rescue" mice that have parathyroid disorders that replicate human hyperparathyroidism. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) determine the role of Sonic hedgehog signaling function and other transcription factor pathway on transcription of the GCM2 gene. Based on our preliminary data, we expect Sonic hedgehog plays a major role in repressing expression of Gcm2 in non-parathyroid cells; and 2) determine the effect of conditional deletion of Gcm2 on the transcriptosome of normal parathyroid glands and on function and size of hyperfunctioning mouse parathyroid glands. We expect that deletion of Gcm2 in normal parathyroid glands will reveal genes that are regulated by Gcm2 and will result in parathyroid atrophy. Moreover, using well-established murine models of primary hyperparathyroidism, we expect that timed deletion of Gcm2 in hyperplastic or adenomatous parathyroid glands will result in decreased survival of parathyroid cells and regression of hyperparathyroidism. The reagents and mouse models are in hand, and the techniques have been established as feasible in the applicants' labs. The approach is innovative because it utilizes novel mouse models, applies new techniques such as enhanced yeast 1-hybrid screening to uncover genes that regulate Gcm2 expression, and uses RNA-seq to develop a comprehensive catalog of the Gcm2-dependent transcriptosome. The proposed research is significant because it is expected to advance our understanding of parathyroid cell biology, and ultimately, to identify molecular targets that will allow development of new medical treatments for primary and tertiary hyperparathyroidism in humans.

描述（由申请人提供）：该重新提交的资助提案是2年ARRA R01资助的结果，该资助产生了新的数据，证明甲状旁腺细胞特异性转录因子Gcm2（胶质细胞缺失2）在甲状旁腺早期胚胎发育后的关键作用，以及该蛋白如何在成熟的甲状旁腺中发挥作用，以控制甲状旁腺细胞的功能和存活。长期目标是利用Gcm2作用的知识，为甲状旁腺功能亢进患者的医学治疗制定新的策略。这个应用程序的目标是确定损耗的程度

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Assessing bone health in children and adolescents.

DOI：
10.4103/2230-8210.104040
发表时间：
2012-12-01
期刊：
Indian journal of endocrinology and metabolism
影响因子：
0
作者：
Levine, Michael A
通讯作者：
Levine, Michael A

Long-Term Safety and Efficacy of Recombinant Human Parathyroid Hormone (1-84) in Adults With Chronic Hypoparathyroidism.

DOI：
10.1210/jendso/bvad043
发表时间：
2023-03-06
期刊：
Journal of the Endocrine Society
影响因子：
4.1
作者：
通讯作者：

Generation of mice encoding a conditional null allele of Gcm2.

DOI：
10.1007/s11248-014-9799-7
发表时间：
2014-08
期刊：
TRANSGENIC RESEARCH
影响因子：
3
作者：
Yuan, Ziqiang;Opas, Evan E.;Vrikshajanani, Chakravarthy;Libutti, Steven K.;Levine, Michael A.
通讯作者：
Levine, Michael A.

Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome.