权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of CRH in skin physiology and pathology

CRH 在皮肤生理学和病理学中的作用

基本信息

批准号：
6801020
负责人：
ANDRZEJ T SLOMINSKI
金额：
$ 23.95万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-01 至 2006-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6801020
关键词：
clinical research corticotropin releasing factor growth /development hair follicle hormone regulation /control mechanism human tissue keratinocyte melanocyte neuroendocrine system neuropeptide receptor physiologic stressor pigmentation proopiomelanocortin receptor binding skin stress tissue /cell culture

项目摘要

DESCRIPTION (provided by applicant): The skin is both target and source for proopiomelanocortin (POMC)-derived neuropeptides. Corticotropin releasing hormone (CRH) and CRH receptors (CRH-R) are also expressed and fully functional in rodent and human skin, but its significance is not known. CRH and CRH receptors are recognized as main central regulators in the response to systemic stress and CRH peptide has pleiotropic role in regulation of local homeostasis. Therefore, we will investigate whether CRH can regulate local expression of POMC gene, mimicking therefore pituitary physiology, and/or to clarify its specific actions in the skin. Within this context, CRH itself is a potent immunomodulatory factor, acts on vascular function, and is also a local growth factor. These actions suggest that in the skin the role of CRH peptide could be pleiotropic in the regulation of local homeostasis. Our initial objective is the biochemical and functional characterization of the CRH-CRH receptor system in mammalian skin. The specific aims are as follow: 1. To define local mechanisms regulating the expression of CRH in normal melanocytes and keratinocytes; 2. To fully characterize the CRH-R1 receptors in normal melanocytes and keratinocytes by a) defining CRH binding site properties, b) measuring production of second messengers including cAMP, IP3 and Ca, c) testing whether postreceptor CRH signal transduction includes activation transcriptional regulators such as NF-kappa beta, CRE, AP1 and STAT; 3. To test the effect of CRH on the production of the POMC mRNA and POMC-derived peptides in normal melanocytes and keratinocytes; 4. To test the phenotypic effect of CRH on normal epidermal melanocytes and keratinocytes; 5. To test CRH participation in regulation of human hair growth and pigmentation. This will be evaluated in human hair follicle grown ex vivo and in isolated sub-populations of hair follicle-derived follicular melanocytes and keratinocytes and dermal papilla cells. To accomplish these goals we will use standard molecular, biochemical, and cell biology tools, which are currently available in our laboratory. As experimental models we will use epidermal and follicular keratinocytes and melanocytes as well as dermal papilla cells. The realization of the above aims should clarify the role of CRH and CRH receptors in the peripheral (skin) response to stress. The core of the project is the realization of the functional biochemical overlap between the cutaneous and hypothalamic CRH-activating systems. Whereas the central interactions between CRH together with CRH-Rs coordinates the behavioral, autonomic and endocrine responses to systemic stress, the present work will test whether that role extends to peripheral organs. Thus, we will test the effects of common stressors on expression of CRH and CRH-Rs, CRH effect on POMC expression. Moreover, we will characterize these CRH receptors and define their role in the regulation of phenotype in the most important components of the epidermis, e.g., melanocytes and keratinocytes, and test the role of CRH/CRH-R1 axis in the regulation of human hair growth.

描述（由申请人提供）：皮肤既是阿黑皮素原（POMC）衍生神经肽的靶点又是来源。促肾上腺皮质激素释放激素（CRH）和CRH受体（CRH-R）也在啮齿动物和人类皮肤中表达并具有完全功能，但其意义尚不清楚。CRH和CRH受体是机体应激反应的主要中枢调节因子，CRH肽在调节局部稳态中具有多效性。因此，我们将研究CRH是否可以调节POMC基因的局部表达，从而模仿垂体生理学，和/或阐明其在皮肤中的特定作用。在这种情况下，CRH本身是一种有效的免疫调节因子，作用于血管功能，也是一种局部生长因子。这些行动表明，在皮肤中的CRH肽的作用可能是多效性的调节局部稳态。我们的初步目标是在哺乳动物皮肤CRH-CRH受体系统的生化和功能特性。具体目标如下：1.目的：1.明确正常黑素细胞和角质形成细胞CRH表达的局部调控机制。通过a）定义CRH结合位点性质，B）测量包括cAMP、IP 3和Ca的第二信使的产生，c）测试受体后CRH信号转导是否包括激活转录调节因子，如NF-κ β、CRE、AP 1和STAT，来充分表征正常黑素细胞和角质形成细胞中的CRH-R1受体; 3.检测CRH对正常黑素细胞和角质形成细胞中POMC mRNA和POMC衍生肽产生的影响; 4.检测CRH对正常表皮黑素细胞和角质形成细胞表型的影响。研究CRH对人毛发生长和色素沉着的调节作用。这将在离体生长的人毛囊中以及在毛囊衍生的毛囊黑素细胞和角质形成细胞和毛乳头细胞的分离亚群中进行评价。为了实现这些目标，我们将使用标准的分子，生物化学和细胞生物学工具，这是目前在我们的实验室。作为实验模型，我们将使用表皮和毛囊角质形成细胞和黑色素细胞以及毛乳头细胞。上述目标的实现应该澄清CRH和CRH受体在外周（皮肤）应激反应中的作用。该项目的核心是实现皮肤和下丘脑CRH激活系统之间的功能生化重叠。而CRH与CRH-Rs之间的中心相互作用协调行为，自主神经和内分泌系统的压力反应，目前的工作将测试这种作用是否延伸到外周器官。因此，我们将测试常见应激对CRH和CRH-Rs表达的影响，CRH对POMC表达的影响。此外，我们将描述这些CRH受体的特征，并确定它们在表皮最重要组成部分表型调节中的作用，例如，黑素细胞和角质形成细胞，并测试CRH/CRH-R1轴在人毛发生长调节中的作用。

项目成果

期刊论文数量（36）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Design, synthesis, and biological action of 20R-hydroxyvitamin D3.

DOI：
10.1021/jm201478e
发表时间：
2012-04-12
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Lu, Yan;Chen, Jianjun;Janjetovic, Zorica;Michaels, Phillip;Tang, Edith K. Y.;Wang, Jin;Tuckey, Robert C.;Slominski, Andrzej T.;Li, Wei;Miller, Duane D.
通讯作者：
Miller, Duane D.

CRH mediates inflammation induced by lipopolysaccharide in human adult epidermal keratinocytes.

CRH 介导成人表皮角质形成细胞中脂多糖诱导的炎症。