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：
10371176
负责人：
KEITH A CHOATE
金额：
$ 52.29万
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 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10371176
关键词：
Affect Area Artificial skin Biochemical Biological Biological Assay Biology Bulla CRISPR/Cas technology Cells Chemicals Childhood Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Cutaneous Data Dermatology Disease Enrollment Epidermis Epithelial Etiology Fissural Foundations Funding Future Generations Genes Genetic Genetic Determinism Genetic study Heat Losses Hereditary Disease Heritability Heterogeneity Ichthyosis Vulgaris In Vitro Individual Infant Infection Investigation Knock-in Knock-out Life Mechanics Medical Records Metabolic Modeling Molecular Morbidity - disease rate Mutation Normal tissue morphology Onset of illness Palmoplantar Keratosis Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Physicians Physiology Population Predisposition Process Proteins Public Health Rare Diseases Reflex action Research Resources Site Skin Surface Technology Tissues Transgenic Organisms Variant Water Work X-Linked Ichthyosis assault cohort comorbidity conditional mutant cost disease phenotype disorders of keratinization exome sequencing experience experimental study gain of function gene discovery gene function genetic disorder diagnosis genetically modified cells genome editing genome sequencing in vivo Model indexing insight keratinocyte kindred loss of function mortality mouse model mutation screening next generation sequencing novel novel strategies pachyonychia congenita prevent reconstitution recruit screening panel self-renewal skin disorder targeted treatment treatment response viral gene delivery

项目摘要

PROJECT SUMMARY: 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. We and others 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 15% of subjects without mutation in known genes. In the last funding period, we identified five new genes for DOK, provided evidence for phenotypic expansion in two others, and identified a novel pathogenesis-directed therapy for one disorder. We now propose to expand our large cohort of well-phenotyped DOK kindreds, to screen for mutations in known causative genes, and to employ exome and genome sequencing in those subjects without mutation in known 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 generate 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 cutaneous function. 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 biologic studies.

项目摘要：角化疾病（DOK）是严重的，罕见的遗传性皮肤疾病，其中中心皮肤的障碍功能被破坏，超增殖的补偿途径为在局部区域或整个皮肤表面激活。这导致了一个严重的折衷的表皮无法充分防止细菌，化学和机械攻击或防止旋转的水分流失。在早期生活中这些疾病可能会危及生命，并且由于起泡而增加了感染的敏感性和裂缝，由于蒸发热量损失和表皮周转率提高，各种相关的合并症和全身性异常，可以在一生中持续存在。我们和其他人已经确定了70多种不同这些疾病的基因，但是临床经验和我们的数据表明，这些基因解释了只有一部分DOK的遗传力，这些遗传力证明了标志性的基因座和表型异质性，在已知基因中没有突变的受试者中有15％以上。在最后资助期，我们确定了DOK的五个新基因，为表型提供了证据另外两个人的扩张，并确定了一种针对一种疾病的新型发病机理指导的疗法。现在，我们建议扩大我们的大量精美的Dok Kindreds，以筛选已知因果基因的突变，并在其中采用外显子组和基因组测序在已知的DOK基因中没有突变的受试者发现这些新的遗传原因疾病。我们将采用患者来源的细胞和组织来询问鉴定出新的基因，并将产生转基因皮肤等效物来研究和证明鉴定突变的发病机理。对于有限数量的新基因而不是以前与DOK有关，我们将使用CRISPR技术生成鼠标模型来进一步检查鉴定突变对皮肤功能的影响。这些研究将继续确定分子途径与表皮分化和自我更新，并将为更详细的未来生物学研究提供关键背景。