Mechanisms of Adrenal Differentiation

肾上腺分化的机制

• 批准号: 7755806
• 负责人: GARY D. HAMMER
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7755806
• 关键词: Activities of Daily Living; Adrenal Cortex; Adrenal Gland Diseases; Adrenal Glands; Cell Cycle; Cells; Cellular biology; Corticotropin; Data; Disease; Future; Gene Targeting; Genes; Genomics; Growth; Hormones; Laboratories; Maintenance; Malignant Neoplasms; Molecular; Organ failure; Pathway interactions; Population; Process; Proliferating; Property; Regulation; Role; SF1; Signal Pathway; Stem cells; System; Therapeutic; Undifferentiated; base; capsule; in vivo; mouse model; novel; programs; public health relevance; response; self-renewal; stem; stem cell niche; transcription factor

DESCRIPTION (provided by applicant): The long range objective of our laboratory is to understand the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification of adrenocortical cells within the adrenal gland. Our strategy for this proposal is to focus on the role of SF1 and the SF1 target gene Dax1 in the regulation of adrenocortical growth maintenance. Based on our preliminary data, we hypothesize that unique transcriptional programs in subcapsular undifferentiated progenitor cells serve to maintain the functional capacity of the adrenal cortex. Our specific aims are directed towards a systematic characterization of novel functions of SF1 critical to this process. We propose to determine the origin of the SF1 positive subcapsular cells (specific aim 1), define the role of Dax1 in the self-renewal and multipotent properties of these adrenocortical cells in vivo (specific aim 2) and determine the mechanisms by which SF1 is activated to initiate a unique proliferation-associated transcriptional profile in this subcapsular population (specific aim 3). The studies proposed here will provide the critical framework for understanding the role of SF1 in adrenocortical stem/progenitor cells in adrenal growth maintenance and lay the groundwork for future therapeutic efforts in diseases of adrenal growth including both hypoplasias and cancer. PUBLIC HEALTH RELEVANCE: Most hormone disorders of the adrenal cortical occur in the context of organ failure or overgrowth. Increasing evidence indicates that the cortex constantly renews its cell population through the constant proliferation of uncommitted cells lying in and/or underneath the outer capsule. Using cellular systems, mouse models together with genomic approaches, we aim to characterize the stem/progenitor cells of the adrenal cortex and uncover the mechanisms by which these cells are regulated by SF1 in normal adrenal growth maintenance. Future efforts are predicted to focus on therapies that target this pathway and downstream genes that are found in the course of these studies to participate in adrenocortical stem/progenitor cell biology.

描述（由申请人提供）：我们实验室的远距离目标是了解信号通路通路和下游转录因子协调肾上腺内肾上腺皮质细胞的规范的细胞和分子机制。我们对该提案的策略是专注于SF1和SF1靶基因DAX1在调节肾上腺皮质增长维持中的作用。基于我们的初步数据，我们假设亚囊的未分化祖细胞中的独特转录程序可维持肾上腺皮质的功能能力。我们的具体目标是针对对这一过程至关重要的SF1新功能的系统表征。我们建议确定SF1阳性亚囊细胞的起源（特定目的1），定义了DAX1在体内这些肾上腺皮质细胞的自我更新和多能特性中的作用（特定目标2），并确定SF1被激活的机制，以激活该机制以启动独特的繁殖相关转录型在该次数中的特定目标（特定于特定的目标3）。这里提出的研究将为了解SF1在肾上腺生长维持中的作用提供关键框架，并为未来的肾上腺疾病疾病（包括呼吸症和癌症）的治疗努力奠定基础。公共卫生相关性：肾上腺皮质的大多数激素疾病发生在器官衰竭或过度生长的背景下。越来越多的证据表明，皮层通过位于外囊下方和/或下方的无办事细胞的恒定增殖来不断更新其细胞群体。使用细胞系统，小鼠模型与基因组方法一起，旨在表征肾上腺皮质的茎/祖细胞，并发现这些细胞在正常肾上腺生长维持中受SF1调节的机制。预计未来的努力将重点放在针对这些途径和下游基因的疗法上，这些疗法和下游基因在这些研究过程中发现了参与肾上腺皮质干/祖细胞生物学的疗法。