Cell specific expression in the pituitary gland

描述(由申请人提供)： 脑下垂体功能障碍会影响生长、生育、应激反应和许多其他身体功能。垂体功能低下可由器官发育中的先天缺陷(约1/4000名新生儿)和垂体腺瘤引起，这是最常见的颅内肿瘤类型之一。治疗包括激素替代疗法，这可能包括每天注射重组生长激素，每个患者的费用都很高。一些腺瘤对药物治疗有反应，而另一些则是复发的，可能会导致毁容、多次经蝶窦手术，并可能导致失明和死亡。基因工程小鼠已经证明了几种转录因子和信号分子在分化中的作用，并且与人类垂体疾病的一致性很突出。在这项资助的前几年，我们定义了四种转录因子在垂体发育和功能中的作用：PITX2、GATA2、FOXL2和LHX3。综上所述，我们对这些转录因子的分析促进了我们对控制脑下垂体器官发生的遗传层次的理解。为了了解先天性垂体发育不全的机制，需要在转录调控因子和细胞周期调控因子之间建立联系。我们建立了一种垂体腺瘤的小鼠基因敲除模型，该模型导致Pou1f1(PIT1)谱系的前体重新招募，以牺牲制造生长激素和催乳素的细胞为代价，产生过量的促甲状腺激素。关于基础促甲状腺激素或肥大和增生的机制，人们知之甚少。这项研究的长期目标是通过了解转录因子如何调节细胞从增殖到分化的转变，以及通过了解干细胞分化为激素产生细胞的过程，来改进对遗传性或获得性垂体功能低下症患者的诊断和治疗。这项应用的总体目标是确定：(目的1)转录因子Pitx2、Lhx3、Lhx4和Isl1的突变如何通过扰乱细胞周期和改变前体细胞增殖到分化的转变而导致垂体腺发育不良，(目的2)什么因素调节Pou1f1谱系向甲状腺激素的分化，以及(3)在甲状腺腺瘤转录组中丰富的选定因子如何在胚胎干细胞系统中显示出分化的功能增强。这项拟议的研究具有创新性，因为它整合了从几种不同的发育不良和增生模型中收集的信息，还因为它将建立一个新的干细胞分化系统。这项研究具有重要意义，因为它将导致发育不全和先天性垂体功能低下的转录因子缺陷与细胞周期中的靶基因联系起来，揭示在正常和异常发育中控制从增殖到分化的分子机制。这些信息将有助于确定人类垂体疾病的基础，包括先天性激素缺乏症和常见的腺瘤。 公共卫生相关性： 脑下垂体被称为“主腺”，因为它控制着许多其他器官的功能，这些器官对生长、繁殖和压力反应都是必不可少的。垂体功能障碍主要有两种形式：新生儿和幼儿由于先天性出生缺陷而缺乏激素分泌，而较大的儿童和成年人由于垂体腺瘤形成而激素分泌不足或过多。虽然激素替代疗法可以成功，腺瘤可以通过药物或手术治疗，但并不是所有的患者都能得到这些方法的帮助。我们建议研究调节垂体器官发育和功能的基因，以期提高人类垂体疾病的诊断和治疗水平。

DESCRIPTION (provided by applicant): Pituitary gland dysfunction affects growth, fertility, the stress response and many other bodily functions. Hypopituitarism can result from congenital defects in organ development (about 1/4000 births) and from pituitary adenomas, which are among the most common type of intracranial tumor. Treatment involves hormone replacement therapy, which can involve daily injections of recombinant growth hormone at great expense per patient. Some adenomas respond to pharmacological therapy, while others are recurrent, potentially causing disfigurement, multiple trans-sphenoidal surgeries, and can result in blindness and death. Genetically engineered mice have proven the roles of several transcription factors and signaling molecules in differentiation, and the correspondence with human pituitary disease is outstanding. In previous years of this grant we defined the roles of four transcription factors in pituitary development and function: PITX2, GATA2, FOXL2, and LHX3. Taken together our analysis of these transcription factors has advanced our understanding of the genetic hierarchy that controls pituitary organogenesis. To understand the mechanisms that underlie congenital pituitary hypoplasia, links need to be made between transcriptional regulators and cell cycle regulators. We established a mouse knockout model of pituitary adenoma that causes recruitment of precursors of the Pou1f1 (PIT1) lineage to produce excess thyrotropes, the pituitary cells that produce thyroid stimulating hormone, at the expense of cells that make growth hormone and prolactin. Little is known about the mechanism of basic thyrotrope specification or the hypertrophy and hyperplasia. The long-term goal of this research is to improve diagnosis and therapy for people with genetic or acquired hypopituitarism by understanding how transcription factors regulate the transition from cell proliferation to differentiation and by understanding the process of stem cell differentiation into hormone producing cells. The overall objective of this application is to determine: (Aim 1) how mutations in the transcription factors Pitx2, Lhx3, Lhx4 and Isl1 cause pituitary hypoplasia by disrupting the cell cycle and altering the transition from precursor cell proliferation to differentiation, (Aim 2) what factors regulate differentiation of the Pou1f1 lineage into thyrotropes, and (3) how selected factors that are enriched in the thyrotrope adenoma transcriptome will exhibit functional enhancement of differentiation in an embryonic stem cell system. The proposed research is innovative because it integrates information gleaned from several different hypoplasia and hyperplasia models and because it will establish a new stem cell differentiation system. This research will be significant because it will link transcription factor defects causing hypoplasia and congenital hypopituitarism to target genes in the cell cycle revealing molecular mechanisms that control the transition from proliferation to differentiation in normal and abnormal development. This information will be informative for identifying the basis for human pituitary diseases including congenital hormone deficiencies and common adenomas. PUBLIC HEALTH RELEVANCE: Lay Narrative The pituitary gland is known as the "master gland" because it controls the function of many other organs that are essential for growth, reproduction, and the stress response. There are two main forms of pituitary dysfunction: lack of hormone production in newborns and young children due to a congenital birth defect and either a deficiency or excess of hormone production in older children and adults due to pituitary adenoma formation. While hormone replacement therapy can be successful and adenomas can be treated pharmacologically or with surgery, not all patients are helped by these methods. We propose to study the genes that regulate pituitary organ development and function with the goal of improving diagnosis and treatment for pituitary disease in humans.