Genetics and Pathobiology of Disorders of Keratinization

角化疾病的遗传学和病理学

基本信息

批准号：
8942911
负责人：
KEITH A CHOATE
金额：
$ 49.82万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-03 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8942911
关键词：
Accounting Affect Area Artificial skin Biochemical Biological Assay Biological Response Modifier Therapy Biology Birth Bulla Cell Culture Techniques Cells Chemicals Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Country Cutaneous Data Development Disease Electron Microscopy Enrollment Epidermis Epithelial Etiology Foundations Future Generations Genes Genetic Genetic Determinism Genetic study Heat Losses Heritability Heterogeneity Histology Histopathology Ichthyoses Ichthyosis Vulgaris Immune In Vitro Individual Infant Infection Investigation Knock-in Mouse Late-Onset Disorder Lead Life Mechanics Medical Records Metabolic Modeling Molecular Morbidity - disease rate Mus Mutate Mutation Pathogenesis Pathway interactions Patients Phenotype Physiological Physiology Predisposition Process Proteins Public Health Rare Diseases Recruitment Activity Registries Reporting Sequence Analysis Skin Surface Syndrome Technology Tissues Transgenic Organisms Water Work X-Linked Ichthyosis assault base cellular transduction cohort cost deafness disease phenotype exome sequencing experience gene discovery genetic disorder diagnosis genetic technology in vivo Model indexing insight keratinization keratinocyte kindred mortality mouse model mutant next generation sequencing novel prevent public health relevance reconstitution research study screening self-renewal skin disorder therapeutic target tool vascular contributions

项目摘要

DESCRIPTION (provided by applicant): Disorders of keratinization (DOK) are severe, rare genetic skin disorders in which the central barrier function of the skin is disrupted and a compensatory pathway of hyper-proliferation is activated in either a localized area or throughout the entire skin surface. This results in a grossly compromised epidermis that fails to adequately protect against bacterial, chemical, and mechanical assault or to prevent transepidermal water loss. In early life, the consequences of these disorders can be life-threatening, with increased susceptibility to infection due to blistering and fissures, dramatically increased metabolic demands due to evaporative heat loss and increased epidermal turnover rate, and various associated comorbid conditions and systemic abnormalities which can persist throughout life. Prior studies have identified over 70 diverse genes for these disorders, yet clinical experience and our data show that these genes explain only a portion of heritability for DOK, which demonstrate marked locus and phenotypic heterogeneity, with greater than 20% of subjects without mutation in known genes. Next generation sequencing has provided a new opportunity to identify genes for DOK, and we have applied it successfully to identify several novel genetic causes of these disorders. We now propose to expand our large cohort of well-phenotyped DOK kindreds, to screen for mutations in common causative genes, and to employ exome sequencing in those subjects without mutation in common DOK genes to discover novel genetic causes of these disorders. We will employ patient-derived cells and tissue to interrogate the function of identified novel genes, and will employ transgenic skin equivalents to study and prove pathogenesis of identified mutations. For a limited number of novel genes not previously implicated in DOK, we will generate mouse models using CRISPR technology to further examine the effect of identified mutations on skin development and physiology. These studies will continue to identify molecular pathways central to the complex processes of epidermal differentiation and self-renewal, and will provide critical context for more detailed future biologc studies.

描述：角质化（DOK）的疾病是严重的，稀有的遗传性皮肤疾病被淘汰，并且在局部区域或整个皮肤表面都激活了高度增殖的补偿途径这些疾病可能是由于起泡和裂缝而导致的，由于蒸发热量损失和表皮周转率的增加而增加了代谢，并且可以持续存在这些疾病，但我们的数据表明，临床经验和我们的数据表明，这是遗传性的一部分叉子托克·托汉（Tohan常见的病因基因的突变，以及在没有突变的那些受试者中的就业组测序，在疾病的常见DOK遗传原因中，我们将采用患者衍生的细胞和组织来质疑已鉴定的新基因的截骨研究和证明对有限的新基因的突变。为更详细的未来生物学研究提供批判性背景。