Role of Prox1 in Murine Pancreas Development

Prox1 在小鼠胰腺发育中的作用

• 批准号: 7263700
• 负责人: Beatriz Sosa-Pineda
• 金额: $ 30.39万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7263700
• 关键词: Address; Adult; Affect; Blood Glucose; Cell physiology; Cells; Communities; Condition; Development; Diabetes Mellitus; Disease; Embryo; Embryonic Development; Endocrine; Enzymes; Epithelial; Equilibrium; Functional disorder; Future; Genetic Programming; Goals; Growth; Homeobox Genes; Homeostasis; Hormones; Human; Islet Cell; Islets of Langerhans; Lead; Malignant neoplasm of pancreas; Mediating; Molecular; Morphogenesis; Morphology; Mouse Strains; Mus; Numbers; Nutritional; Organ; Organogenesis; Pancreas; Pancreatic Diseases; Pancreatitis; Pathologic; Pathway interactions; Physiology; Prevention; Process; Research; Research Personnel; Role; Staging; Tissues; blood glucose regulation; computerized data processing; embryo tissue; functional loss; gene function; in utero; novel; postnatal; precursor cell; prevent; programs; tool; transcription factor

DESCRIPTION (provided by applicant): Pancreas development requires different signaling processes and the concerted activities of various transcription factors. Remarkably, some of the key molecular components of pancreatic diseases are also critical regulators during normal pancreas organogenesis. Thus, unraveling the intricate molecular machinery regulating mammalian pancreas development is necessary not only to understand the origins of pancreatic dysfunction, but also to develop tools for better treatment and prevention of pancreatic diseases. Our initial studies on Prox1 identified this transcription factor as a crucial, novel regulator of multiple processes during early pancreas organogenesis. First and foremost, our studies showed that in developing pancreatic tissues the activity of Prox1 enables epithelial growth and morphogenesis. In addition, Prox1 appears to be a crucial component of a genetic program that is destined to produce the cellular complexity of the mammalian pancreas (Wang et al., 2005). Unfortunately, our previous studies could not determine how the lack of Prox1 activity affects overall pancreas organogenesis, how this deficiency affects pancreatic function, or whether Prox1 activity is necessary in ¿ cells to maintain blood glucose homeostasis, because Prox1-nullizygous embryos die in utero. In order to answer these important questions, in this proposal we put forward several experimental approaches to uncover the molecular mechanism of Prox1 function in developing pancreatic tissues of mice, to investigate how the loss of Prox1 function affects pancreas homeostasis at postnatal stages; and to determine if Prox1 function is required for ¿ cell function. After concluding the experimental approaches outlined in this proposal I expect to have uncovered important, novel functions of Prox1 in pancreatic tissues of embryos or adults; to obtain valuable information on the cellular and molecular mechanisms controlled by Prox1 in developing pancreatic tissues; and to generate several novel strains of mice that could be valuable to the scientific community for future studies. The ultimate goal of our research is to contribute to disclose the molecular origin of human pancreatic diseases, and to develop novel therapies to overcome those diseases.

描述（由申请人提供）：胰腺发育需要不同的信号传导过程和各种转录因子的协同活性。值得注意的是，胰腺疾病的一些关键分子组分也是正常胰腺器官发生过程中的关键调节剂。因此，解开调节哺乳动物胰腺发育的复杂分子机制不仅对于了解胰腺功能障碍的起源是必要的，而且对于开发更好地治疗和预防胰腺疾病的工具也是必要的。我们对Prox 1的初步研究将这种转录因子确定为早期胰腺器官发生过程中多个过程的重要的新型调节因子。首先，我们的研究表明，在发育中的胰腺组织中，Prox 1的活性使上皮生长和形态发生成为可能。此外，Prox 1似乎是注定产生哺乳动物胰腺的细胞复杂性的遗传程序的关键组分（Wang et al.，2005年）。不幸的是，我们以前的研究无法确定Prox 1活性的缺乏如何影响整个胰腺器官的形成，这种缺乏如何影响胰腺功能，或者Prox 1活性是否是维持血糖稳态所必需的，因为Prox 1-nullizygous胚胎在子宫内死亡。为了回答这些重要的问题，我们提出了几种实验方法来揭示Prox 1功能在小鼠胰腺组织发育中的分子机制，研究Prox 1功能的丧失如何影响出生后阶段的胰腺稳态;并确定Prox 1功能是否是细胞功能所必需的。在总结了本提案中概述的实验方法后，我希望能够发现Prox 1在胚胎或成人胰腺组织中的重要的新功能;获得有关Prox 1在发育胰腺组织中控制的细胞和分子机制的有价值的信息;并产生几种对科学界未来研究有价值的新型小鼠品系。我们研究的最终目标是有助于揭示人类胰腺疾病的分子起源，并开发新的治疗方法来克服这些疾病。