Investigation into the role of HOX factors in gonad and adrenal steroidogenesis

HOX因子在性腺和肾上腺类固醇生成中的作用研究

• 批准号: G0901645/1
• 负责人: Amanda Swain
• 金额: $ 48.78万
• 依托单位: Institute of Cancer Research
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0901645%2F1
• 关键词: Investigation; into; role; HOX; factors

The gonad and adrenal cortex are derived from a common progenitor cell population and actively produce steroids during embryonic development. The regulation of steroid production in these organs and the factors that account for steroid specificity are not well understood. In this proposal we aim to investigate the role of members of the HOX family of transcription factors in the regulation of steroid production in the gonad and adrenal. HOX factors have been shown to regulate patterning in the embryo and our preliminary experiments indicate that they contribute to organ specific steroid production. We have identified HOXB9 as being expressed in the adrenal cortex but not the gonad and, conversely, we have identified HOXD9 as being gonad, but not adrenal, specific. Misexpression of HOXB9 in the gonad of transgenic mice gave rise to an increase in the presence of genes encoding enzymes involved in adrenal specific steroid production. We plan to use a combination of approaches including analysis of transgenic mice and tissue and organ culture experiments to determine the role of these HOX factors in steroidogenesis. As an extension of these studies we will investigate the ability of HOXB9 to cooperate with the nuclear hormone receptor SF-1 to induce the differentiation of adrenal steroid production in embryonic stem (ES) cells. SF-1 is a nuclear hormone receptor that has been shown to be required for the differentiation of steroid producing cells of the gonad and adrenal and can induce some aspects of steroid production in ES cells. Our studies will further these observations and may provide a framework for the production of steroid producing cells that may contribute to the development of novel therapies for patients with adrenal and gonadal failure.

性腺和肾上腺皮质来自共同的祖细胞群，并在胚胎发育期间积极产生类固醇。这些器官中类固醇产生的调节和类固醇特异性的因素还不清楚。在这个建议中，我们的目的是调查的作用，HOX家族的转录因子在调节类固醇生产的性腺和肾上腺。HOX因子已被证明可以调节胚胎中的模式，我们的初步实验表明它们有助于器官特异性类固醇的产生。我们已经确定HOXB 9在肾上腺皮质中表达，而不是性腺，相反，我们已经确定HOXD 9是性腺特异性的，而不是肾上腺特异性的。在转基因小鼠的性腺中HOXB 9的错误表达引起编码参与肾上腺特异性类固醇产生的酶的基因的存在增加。我们计划使用包括转基因小鼠和组织器官培养实验分析的方法相结合，以确定这些HOX因子在类固醇生成中的作用。作为这些研究的延伸，我们将研究HOXB 9与核激素受体SF-1合作诱导胚胎干细胞（ES）中肾上腺类固醇产生分化的能力。SF-1是一种核激素受体，已被证明是性腺和肾上腺的类固醇产生细胞分化所需的，并且可以诱导ES细胞中类固醇产生的某些方面。我们的研究将进一步这些观察，并可能提供一个框架，为生产类固醇生产细胞，可能有助于开发新的治疗肾上腺和性腺功能衰竭的患者。