Pathogenesis and Therapy of Ichthyosis in Disorders of Lipid Metabolism

脂质代谢紊乱引起的鱼鳞病的发病机制和治疗

• 批准号: 10348673
• 负责人: Theodora M Mauro
• 金额: $ 33.39万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348673
• 关键词: Acyltransferase; Alopecia; Animal Model; Appearance; Applications Grants; Biochemical; Biochemical Genetics; Biopsy; Biopsy Specimen; Bypass; CRISPR/Cas technology; Cell Line; Ceramides; Cholesterol; Cholesterol Homeostasis; Clinical; Clinical Research; Cutaneous; DNA Sequence Alteration; Defect; Disease; Distal; Distant; Down-Regulation; Dreams; Environment; Enzyme Inhibitor Drugs; Epidermis; Essential Fatty Acids; Excision; Exfoliative Dermatitis; Face; Fatty Acids; Fibroblasts; Future; Generations; Genes; Genetic; Genotype; Human; Ichthyoses; Induced Mutation; Inherited; Knockout Mice; Lead; Life; Limb structure; Link; Lipids; Metabolic; Metabolic Diseases; Metabolism; Modeling; Mutation; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Permeability; Phenotype; Photophobia; Production; Refsum Disease; Rho-associated kinase; Risk; Site; Skin; Small Interfering RNA; Stratum corneum; Syndrome; Technology; Therapeutic; Translating; Translations; Treatment Efficacy; base; canine model; cost; cytotoxic; cytotoxicity; disease phenotype; effective therapy; extracellular; gene replacement therapy; gene therapy; improved; inhibitor; keratinocyte; kinase inhibitor; lipid disorder; lipid metabolism; monolayer; mouse model; novel strategies; premature; prevent; response; scaffold; skin lesion; transcriptome sequencing

Current therapy of the ichthyoses, including the lipid synthetic, autosomal recessive congenital ichthyoses (ARCI), is largely symptomatic, and often irrational; e.g., when removal of excess scale interferes with homeostatic responses that allow patients to survive in a harsh, terrestrial environment. At the other extreme, corrective gene therapy, though seductive in concept, remains a distant dream, with many potential pitfalls. Our proposed new approach has been first, to identify pathogenic mechanisms in ARCI patients, using biopsies from patients and animal models, as well as organotypic models (HEEs) of the ARCI, prepared from either patient fibroblast or keratinocyte cell lines, or from normal fibroblasts by CRISPR/Cas 9 technology. Using ultrastructural, lipid biochemical, and RNA-seq technology, we will assess both the cellular and genetic basis for these disorders, and identify compensatory mechanisms that account for patient survival. We then will assess whether this new information can translate into readily-deployable, topical therapies for patients after their initial optimization in ARCI HEEs, and in disease-appropriate animal models. Following identification and optimization of effective therapy in the animal models, we will initiate clinical studies for these patients, supported by a parallel grant proposal. If successful, this approach should initiate a paradigm shift in how many of the ichthyoses will be treated in the future. Finally, since the cutaneous phenotype reflects pathogenic mechanisms that also are on-going in syndromic disorders with extracutaneous disease manifestations, successful pathogenesis-based therapy for these ARCI could also identify comparable approaches to treat/prevent the extracutaneous manifestations of these disorders.

鱼鳞病包括脂质合成型常染色体隐性遗传性先天性鱼鳞病的治疗现状 （ARCI），在很大程度上是症状性的，而且往往是不合理的;例如，当去除多余的水垢干扰 使病人能在严酷的陆地环境中生存的自我平衡反应。在另一个极端， 矫正性基因治疗虽然在概念上很诱人，但仍是一个遥远的梦想，有许多潜在的陷阱。 我们提出的新方法是第一个，以确定致病机制，在ARCI患者，使用 来自患者和动物模型的活组织检查，以及ARCI的器官型模型（HEE）， 患者成纤维细胞或角质形成细胞细胞系，或通过CRISPR/Cas 9技术来自正常成纤维细胞。 使用超微结构，脂质生化和RNA-seq技术，我们将评估细胞和遗传 这些疾病的基础，并确定补偿机制，占病人的生存。然后我们将 评估这些新信息是否可以转化为易于部署的局部治疗， 它们在ARCI HEE和疾病适当的动物模型中的初始优化。在识别和 在动物模型中优化有效治疗，我们将启动这些患者的临床研究， 由一个平行的赠款提案支持。如果成功的话，这种方法应该会引发一种范式转变， 的鱼鳞病将在未来得到治疗。最后，由于皮肤表型反映了致病性 在具有皮外疾病表现的综合征性疾病中也正在进行的机制， 对这些ARCI成功的基于发病机制的治疗也可以确定类似的方法， 治疗/预防这些疾病的皮外表现。

项目成果

Ichthyosis vulgaris: the filaggrin mutation disease.

• DOI: 10.1111/bjd.12219
• 发表时间: 2013-06
• 期刊: The British journal of dermatology
• 作者: Thyssen JP;Godoy-Gijon E;Elias PM
• 通讯作者: Elias PM

Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis.

• DOI: 10.1016/j.jaci.2014.05.048
• 发表时间: 2014-10
• 期刊: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
• 影响因子: 14.2
• 作者: Elias, Peter M.;Wakefield, Joan S.
• 通讯作者: Wakefield, Joan S.

Cetacean epidermal specialization: A review.

• DOI: 10.1111/ahe.12829
• 发表时间: 2022-09
• 期刊: Anatomia, histologia, embryologia

Alterations in epidermal function in type 2 diabetes: Implications for the management of this disease.

• DOI: 10.1111/1753-0407.13303
• 发表时间: 2022-09
• 期刊: Journal of diabetes
• 影响因子: 4.5

Role of nitric oxide in regulating epidermal permeability barrier function.

• DOI: 10.1111/exd.14470
• 发表时间: 2022-03
• 期刊: Experimental dermatology
• 影响因子: 3.6
• 作者: Man MQ;Wakefield JS;Mauro TM;Elias PM
• 通讯作者: Elias PM