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：
10211211
负责人：
KEITH A CHOATE
金额：
$ 51.35万
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/10211211
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.

项目概要：角化障碍 (DOK) 是一种严重、罕见的遗传性皮肤病，其中中枢皮肤的屏障功能被破坏，过度增殖的补偿途径被破坏在局部区域或整个皮肤表面激活。这导致严重受损的表皮无法充分抵御细菌、化学物质和机械攻击或防止经皮水分流失。在生命的早期，后果这些疾病可能会危及生命，并且由于起泡而增加感染的可能性和裂缝，由于蒸发热损失和代谢需求急剧增加表皮更新率增加，以及各种相关的合并症和全身性疾病可能持续一生的异常。我们和其他人已经确定了 70 多个不同的这些疾病的基因，但临床经验和我们的数据表明这些基因解释仅 DOK 遗传力的一部分，显示出明显的位点和表型异质性，超过 15% 的受试者已知基因没有突变。在最后资助期间，我们鉴定了5个DOK新基因，为表型提供了证据在另外两种疾病中进行了扩展，并确定了一种针对一种疾病的新型发病机制导向疗法。我们现在建议扩大我们大量表型良好的 DOK 亲属，以筛选已知致病基因的突变，并在这些基因中采用外显子组和基因组测序已知 DOK 基因没有突变的受试者，以发现这些疾病的新遗传原因失调。我们将利用患者来源的细胞和组织来探究其功能确定了新基因，并将生成转基因皮肤等效物以进行研究和证明已识别突变的发病机制。对于以前没有的有限数量的新基因涉及DOK，我们将利用CRISPR技术生成小鼠模型以进一步检查已识别的突变对皮肤功能的影响。这些研究将继续识别表皮分化复杂过程的核心分子途径自我更新，并将为未来更详细的生物学研究提供关键背景。