The derivation of pituitary cells from human ES cells

从人类 ES 细胞衍生垂体细胞

基本信息

批准号：
9068845
负责人：
VIVIANE TABAR
金额：
$ 19.13万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9068845
关键词：
Achievement Address Animals Anterior Pituitary Hormones Attention Behavioral Biological Assay Brain Cancer Patient Cancer Survivor Cell Therapy Cells Child Clinical Collaborations Complex Cranial Irradiation Data Data Set Derivation procedure Disease remission Dose Endocrine Endocrine Glands Environment Etiology Female Functional disorder Future Gene Expression Gland Goals Graft Survival Grant Growth Health Hormonal Hormones Human Hypophysectomy Hypopituitarism Hypothalamic structure In Vitro Infection Injury Malignant Neoplasms Measurement Measures Modeling Nature Neurosecretory Systems Nude Rats Organism Phenotype Pituitary Gland Plasma Production Protocols documentation Quality of life Radiation Radiation Injuries Radiation therapy Rattus Reporter Reproductive Behavior Research Personnel Role Serum Site Solid Surgical Models Survivors Technology Testing Therapeutic Time Traumatic Brain Injury Validation Weight Work base clinically relevant design drug discovery high risk human embryonic stem cell hypothalamic pituitary axis in vivo induced pluripotent stem cell insight interest novel precursor cell research study young adult

项目摘要

DESCRIPTION (provided by applicant): This proposal aims at designing a cell-therapy based approach to hypopituitarism , with special focus on pituitary dysfunction due to radiation injury. The pituitary gland is a master endocrine organ that orchestrates the function of multiple glands in the organism, under direct control by the hypothalamus. Hypopituitarism is a very prevalent problem following radiation treatment to the brain. It is dose-related, progressive and irreversible; it also contributes to poor quality of life and other substantial problems among cancer survivors. Hypopituitarism is also an important permanent consequence of infection, traumatic brain injury or congenital conditions. We have developed a protocol for the specification of pituitary cells from human ES cells and further differentiation into hormone producing cells. We have also previously optimized a brain radiation model in the rat, using a clinically relevant fractionated radiation course. The animals are well studied for growth, weight and behavioral parameters and we have some preliminary evidence of pituitary dysfunction. Here we propose to optimize the human ES and iPS differentiation protocol to allow the enrichment into specific pituitary cell subtypes. Validation of cell phenotypes is obtained through gene expression and marker profiles, measurements of hormone secretions, as well as in vivo function. Human ES derived pituitary cells are grafted into hypophysectomized nude rats and basal hormone levels are measured in the serum at different time points. Grafts will be placed subcutaneously or orthotopically into the hypothalamus / pituitary interface. We will also graft the cells into the irradiated rats with evidence of pituitary damage. Analysis will focus on revovery of hormone levels in the plasma, as well as evidence of integration of the graft into the hypothalamic - pituitary axis, using stimulation tests. Furthermore, functional analysis will be attempted by asking whetehjr female rats with cell grafts can recover their ability to reproduce and lactate.The proposal addresses a novel problem that has received little attention to date. As we succeed in achieving long term remission among cancer patients, questions of poor quality of life among survivors have acquired a more pressing nature. This project will provide much needed insight into the feasibility of cell based therapy to ameliorate these consequences of brain radiation. It will also undertake the derivation of specific pituitary cell subtypes from humn ES or iPS cells, an unreported achievement in human cells to date.

描述（由适用提供）：该提案旨在设计基于细胞治疗的肌次尿素主义的方法，特别关注由于放射线损伤而引起的垂体功能障碍。垂体是一种主内分泌器官，在下丘脑的直接控制下，在生物体中策划了多个腺体的功能。在辐射治疗大脑后，肌次症是一个非常普遍的问题。它是与剂量有关的，进行的和不可逆的；它还导致生活质量差和癌症生存中的其他实质性问题。垂体不足也是感染，创伤性脑损伤或先天性状况的重要永久性结果。我们已经开发了一项方案，用于指定人类ES细胞的垂体细胞，并进一步分化为雌激素生产细胞。我们先前使用临床相关的分离辐射疗程，以前还使用了大鼠中的大脑辐射模型。对动物的生长，体重和行为参数进行了很好的研究，我们有一些垂体功能障碍的初步证据。在这里，我们建议优化人类ES和IPS分化方案，以使富集成特定的垂体细胞亚型。细胞表型的验证是通过基因表达和标记谱，雌马分泌的测量以及体内功能。人ES衍生的垂体细胞被接枝到腹部裸鼠中，在不同时间点在血清中测量了基本的同位水平。移植物将皮下或原位放置在下丘脑 /垂体界面中。我们还将用垂体损伤的证据将细胞分为受辐照的大鼠。分析将侧重于血浆中马酮水平的恢复，以及使用刺激测试将移植物整合到下丘脑 - 垂体轴上的证据。此外，通过询问具有细胞移植物的雌性大鼠可以恢复其繁殖和划分的能力来尝试进行功能分析。该提案解决了迄今为止很少关注的新问题。随着我们成功地在癌症患者中长期缓解时，幸存者生活质量差的问题已经获得了更加紧迫的性质。该项目将提供急需的洞察力，以了解基于细胞的疗法可以改善脑辐射的这些后果。它还将从湿ES或IPS细胞中衍生出特定的垂体细胞亚型，这是迄今为止人类细胞中未报告的成就。