Mechanism of CTIP2 action in mouse epidermal homeostasis and barrier formation,

描述（由申请人提供）：皮肤从宫内到宫外的发育是表皮增生、终末分化和屏障形成的精心安排的相互作用。对于大多数早产儿来说，表皮通透性屏障（EPB）的构建失败是一个危及生命的问题，它会导致经皮失水增加，同时伴有脱水和电解质失衡，以及皮肤脆弱。屏障缺陷也被认为有助于一些遗传性和获得性炎症性皮肤病，如牛皮癣和特应性皮炎（AD）。因此，了解皮肤中由不同调节蛋白（如转录因子）控制的途径是开发有效治疗上述各种皮肤病以及包括头颈部鳞状细胞癌（HNSCC）在内的上皮细胞皮肤癌的关键。鸡卵白蛋白上游启动子转录因子(COUP-TF)-相互作用蛋白2 （CTIP2，也称为Bcl11b）是一种转录调节蛋白，在小鼠发育过程中在皮肤以及成年小鼠增殖细胞中高度表达。我们最近发现，小鼠种系CTIP2缺失会导致严重的皮肤表型，其特征是EPB形成受损，表皮厚度显著减少。我们还在几个人HNSCC活检中观察到CTIP2的显著上调，其中CTIP2的表达水平与肿瘤的分化程度呈负相关，即发现低分化肿瘤表达非常高水平的CTIP2，而高分化肿瘤表达非常少的CTIP2。然而，在表皮稳态和屏障形成过程中，CTIP2在皮肤中活性的细胞和分子机制尚不清楚。同样，我们不了解CTIP2在皮肤发育过程中的增生性事件或成人增生性疾病（如HNSCC）中的作用。缺乏这方面的知识是我们理解CTIP2在人类健康和疾病中的生物学作用的一个关键问题。该实验室的长期目标是阐明CTIP2在胎儿、新生儿和成人皮肤以及皮肤增生性疾病中的作用的分子和细胞机制，以实现将其推广到人类情况的目标。基于以上观察和初步数据，我们提出以下三个具体目的：(1)阐明CTIP2在EPB形成中的细胞和分子机制；(2)阐明CTIP2在表皮增殖/分化中的细胞和分子机制；(3)确定CTIP2在头颈部鳞状细胞癌发病机制中的作用。这项提议的研究具有创新性，因为它将首次揭示CTIP2调节皮肤器官发生、EPB形成和组织稳态的细胞和分子机制。我们相信，这项研究将对人类健康产生重大的积极影响，因为这些结果将提供对表皮角化细胞增殖、分化和EPB形成的调节作用的更好理解，这可能导致开发更有效的治疗人类疾病的范例，如特应性皮炎，可能还有HNSCC。

DESCRIPTION (provided by applicant): The development of the skin from intrauterine to extrauterine life is an orchestrated interplay of epidermal proliferation, terminal differentiation, and barrier formation. Failure to construct an epidermal permeability barrier (EPB), which is a life-threatening problem in the majority of premature infants, results in increased transepidermal water loss with concomitant dehydration and electrolyte imbalance, as well as fragile skin. Barrier defects are also believed to contribute to several hereditary and acquired inflammatory skin disorders, such as psoriasis and atopic dermatitis (AD). Thus, understanding the pathways that are controlled by different regulatory proteins (e.g., transcription factors) in skin is the key for the development of effective treatments for the various skin diseases described above, as well as epithelial cell skin cancers, including head and neck squamous cell carcinoma (HNSCC). Chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2 (CTIP2, also known as Bcl11b) is a transcriptional regulatory protein that is highly expressed in skin during mouse development, as well as in proliferating cells of the adult mouse. We have recently discovered that germline deletion of CTIP2 in mice results in a severe skin phenotype characterized by compromised EPB formation, and dramatically reduced epidermal thickness. We have also observed striking upregulation of CTIP2 in several human HNSCC biopsies, in which the level of CTIP2 expression was inversely correlated with the degree of differentiation of the tumor, i.e., poorly differentiated tumors were found to express very high levels of CTIP2 while highly differentiated tumors expressed very little CTIP2. However, the cellular and molecular mechanism underlying the activity of CTIP2 in skin during epidermal homeostasis and barrier formation is not known. Similarly, we do not understand the role of CTIP2 in proliferative events during skin development or in proliferative diseases of adults, such as HNSCC. Lack of this knowledge is a critical problem in our understanding of the biological roles of the CTIP2 in human health and disease. The long-term goal of this laboratory is to elucidate the molecular and cellular mechanisms that underlie the actions of CTIP2 in fetal, neonatal, and adult skin, and in proliferative diseases of the skin, towards the goal of extrapolating to the human situation. Based on the above observations and from the preliminary data, we propose the following three Specific Aims: (1) to elucidate the cellular and molecular mechanism(s) underlying the role of CTIP2 in EPB formation, (2) to elucidate the cellular and molecular mechanism(s) of CTIP2 action in epidermal proliferation/differentiation, and (3) to determine the role of CTIP2 in pathogenesis of head and neck squamous cell carcinoma. The proposed research is innovative because it will, for the first time, reveal the cellular and molecular mechanisms by which CTIP2 regulates skin organogenesis, EPB formation, and tissue homeostasis. We believe that this research will have significant, positive effects on human health because these outcomes will provide an enhanced understanding of regulatory influences on epidermal keratinocyte proliferation, differentiation and EPB formation, which may lead to development of more efficacious treatment paradigms for the human disorders, such as atopic dermatitis, and possibly HNSCC.