Mechanisms of differentiation changes in skin disease and malignancy

描述（由申请人提供）：上皮细胞，如皮肤表皮，以刻板分化程序为特征，其中干细胞群体在增殖和组织特异性分化之间保持谨慎的平衡。这种平衡的中断会严重损害皮肤的功能，并导致各种疾病状态。许多皮肤病如表皮松解性角化过度症（EH）、牛皮癣和鱼鳞病都与异常分化有关1,2,3皮肤鳞状细胞癌（SCC）中也可见分化的变化，相反，许多皮肤屏障受损的疾病（如EH）导致过度增殖，增加SCC的易感性。虽然SCCs最常见于皮肤，但也见于许多其他分层鳞状上皮组织，如肺、头部、颈部、乳房和阴道。通常，这些肿瘤的分化程度是患者预后的一个预测指标。4,5,6深入了解分化是如何在发育过程中建立并在组织稳态中维持的，有助于深入了解各种皮肤病的发病机制。一个多世纪以来，未分化的肿瘤外观一直是临床医生观察到的一个很好的特征。尽管存在这种相关性，但分化变化在恶性肿瘤，特别是实体瘤的进展中所起的作用尚不清楚。在皮肤中，分化程序是在定型发育时期建立的，此时单层立方体细胞转变为生命必需的复杂层状上皮。我的研究重点是阐明表皮发育过程中自然发生的变化，以了解与皮肤疾病（如SCC）相关的变化如何影响分化程序。这项工作将阐明这些变化中的扰动在疾病进展中所起的作用。答案应该阐明恢复适当分化程序的方法是否可能为对抗鳞状细胞癌（SCC）的发展提供新的途径。我的目标首先是阐明与表皮干细胞相关的复杂转录谱，因为表皮干细胞分层、分化并形成成熟的皮肤组织，并形成一个屏障来阻止微生物进入并保留体液。接下来，我将研究已知与SCC恶性肿瘤相关的基因表达变化如何影响这种分化程序。最后，我的目的是了解与鳞状细胞癌相关的分化变化如何影响肿瘤的发生和进展。

DESCRIPTION (provided by applicant): Epithelia such as the epidermis of the skin are characterized by stereotyped differentiation programs where populations of stem cells are maintained in a careful equilibrium between proliferation and tissue-specific differentiation. Interruption of this balance significantly impairs the function of the skin and results in variety f disease states. Many skin diseases such as epidermolytic hyperkeratosis (EH), psoriasis and ichthyosis are associated with abnormal differentiation.1,2,3 Changes in differentiation are also seen in squamous cell carcinoma (SCC) of the skin, and conversely, many disorders in which the skin barrier is compromised (e.g. EH) lead to excessive proliferation, increasing SCC susceptibility. Though most prevalent in the skin, SCCs occur in many other stratified squamous epithelial tissues such as those of lung, head, neck, breast and vagina. Often, the degree of differentiation of these tumors is a predictor of patient prognosis. 4,5,6 A deeper understanding of how differentiation is established during development and maintained during tissue homeostasis provides insight into the pathogenesis of a variety of skin disease causing significant morbidity. Anaplasia, or the undifferentiated appearance of a tumor, has been a well characterized observation of clinicians for over a century. Despite this correlation the role that changes in differentiation play in progression of malignancies, particularly of solid tumors, is no clear. In the skin the differentiation program is established during a stereotyped developmental period where a single layer of cuboidal cells transforms into a complex layered epithelium essential for life. My study focuses on elucidating the changes that naturally occur during epidermal development in order to understand how changes associated with skin diseases such as SCC affect the differentiation program. This work will clarify what role perturbations in these changes play in disease progression. The answers should illuminate whether methods to restore the proper differentiation program might present a new avenue to combat development of squamous cell carcinoma (SCC). I aim first to elucidate the complex transcriptional profiles associated with epidermal stem cells as they stratify, differentiate and form mature skin tissue with a barrier to keep microbes out and retain body fluids. Next I will investigate how the gene expression changes that are known to be associated with SCC malignancy affect this differentiation program. Finally I aim to understand how the differentiation changes associated with squamous cell carcinoma affect tumor initiation and progression.