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

基本信息

批准号：
9041538
负责人：
Peter M Elias
金额：
$ 33.35万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9041538
关键词：
Accounting Affect Animal Model Appearance Applications Grants Biochemical Process Biopsy Cell membrane Cell physiology Cholesterol Cholesterol Homeostasis Clinical Clinical Research Coupled Cutaneous DNA Sequence Alteration Defect Disease Distal Distant Doctor of Medicine Dreams Drug Delivery Systems Environment Enzyme Inhibitor Drugs Enzyme Inhibitors Epidermis Excision Exfoliative Dermatitis Functional disorder Future Ichthyoses Inborn Genetic Diseases Individual Inherited Injection of therapeutic agent Lanosterol Lead Limb structure Lipids Lovastatin Metabolic Metabolic Diseases Mutation Pathogenesis Pathway interactions Patients Permeability Pharmaceutical Preparations Phenotype Production Severities Simvastatin Skin Syndrome Therapeutic Tissues Toxic effect Translating Translations Treatment Efficacy Work X-Linked Ichthyosis base clinical phenotype cost disease phenotype effective therapy gene therapy improved in vitro Model insight lipid disorder lipid metabolism novel prevent repaired response skin disorder synthetic enzyme

项目摘要

DESCRIPTION (provided by applicant): Current therapy of the Ichthyoses is purely 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 approach will be first, to identify pathogenic mechanisms in patients, and then to assess whether this new information can be translated into readily-deployable, topical therapy in disease-appropriate animal models. Initially, we will study Ichthyosis pathogenesis (in patients and relevant animal models) with inherited, syndromic disorders of distal cholesterol metabolism (Group I disorders) where the cutaneous phenotype can range from severe (as in CHILD syndrome, lathosterolosis, and SC4MOL deficiency), to moderately-severe (as in CHH), or mild-to-inapparent (as in SLOS and desmosterolosis). Then, we will translate mechanistic insights into potentially-effective therapies in relevant animal models. This pathogenesis-based approach then will be extended to patients (and animal models) of other syndromic disorders of lipid metabolism (Group II). Following identification and optimization of effective therapy in the animal models, we will launch clinical studies for these patients, as part of 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 extracutaneous tissues, successful pathogenesis-based therapy for the Ichthyoses could point to comparable approaches to treat/prevent the extracutaneous manifestations of these disorders.

描述（由申请人提供）：目前鱼鳞病的治疗纯粹是针对症状的，而且往往是不合理的；例如，当去除多余的水垢会干扰体内平衡反应时，使患者能够在恶劣的陆地环境中生存。在另一个极端，纠正性基因疗法虽然在概念上很诱人，但仍然是一个遥远的梦想，存在许多潜在的陷阱。我们的方法首先是确定患者的致病机制，然后评估这些新信息是否可以转化为在适合疾病的动物模型中易于部署的局部治疗。首先，我们将研究具有遗传性远端胆固醇代谢综合征（I 类疾病）的鱼鳞病发病机制（在患者和相关动物模型中），其中皮肤表型的范围可以从严重（如儿童综合征、斑甾醇病和 SC4MOL 缺乏症），至中重度（如 CHH），或轻度至不明显（如 SLOS 和去睾酮症）。然后，我们将把机制见解转化为相关动物模型中潜在有效的疗法。这种基于发病机制的方法将扩展到其他脂质代谢综合征（第二组）的患者（和动物模型）。在动物模型中确定和优化有效疗法后，我们将为这些患者启动临床研究，作为并行拨款提案的一部分。如果成功的话，这种方法应该会在未来治疗多少鱼鳞病方面引发范式转变。最后，由于皮肤表型反映了皮外组织中也在发生的致病机制，因此成功的基于发病机制的鱼鳞病治疗可能会为治疗/预防这些疾病的皮外表现提供类似的方法。