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：
8434177
负责人：
Peter M Elias
金额：
$ 31.68万
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/8434177
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 Defect Disease Distal Distant Doctor of Medicine Dreams Drug Delivery Systems Environment Enzyme Inhibitor Drugs Enzyme Inhibitors Epidermis Excision Exfoliative Dermatitis Functional disorder Future Gene Mutation 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

Accounting Affect Animal Model Appearance Applications Grants Biochemical Process Biopsy Cell membrane Cell physiology Cholesterol Cholesterol Homeostasis Clinical Clinical Research Coupled Cutaneous Defect Disease Distal Distant Doctor of Medicine Dreams Drug Delivery Systems Environment Enzyme Inhibitor Drugs Enzyme Inhibitors Epidermis Excision Exfoliative Dermatitis Functional disorder Future Gene Mutation 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

展开

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）：鱼类的当前治疗纯粹是症状，通常是不合理的；例如，当去除过度规模时，会干扰稳态反应，使患者能够在恶劣的陆地环境中生存。在另一个极端的，纠正的基因疗法虽然在概念上诱人，但仍然是一个遥远的梦想，具有许多潜在的陷阱。我们的方法将首先是确定患者的致病机制，然后评估是否可以将这些新信息转化为适合疾病的动物模型中容易养生的局部疗法。最初，我们将使用遗传性的胆固醇代谢远端综合症疾病（I组疾病（I组疾病）研究鞘膜炎发病机理（在患者和相关动物模型中），皮肤表型可能范围从严重（如儿童综合征，lathostropersis和Sc4-c4-collinity）到适度的SLEAPS，或者与SLEAPTER-SLEAPTER（或SLEAPTAIN-SLEAPTAIL-CHHHH）一样，或者在CHHHHHHS中，或降霉菌病）。然后，我们将将机械洞察力转化为相关动物模型中潜在有效的疗法。然后，这种基于发病机理的方法将扩展到脂质代谢的其他综合症患者（II组）的患者（和动物模型）。在鉴定和优化动物模型中有效治疗后，我们将为这些患者启动临床研究，这是平行赠款提案的一部分。如果成功的话，这种方法将启动范式转变，以将来对待多少个鱼类。最后，由于皮肤表型反映了在紧急组织中也正在进行的致病机制，因此针对鱼类的基于发病机理的成功治疗可以指出可比较的方法来治疗/预防这些疾病的外部表现。