Ubiquitin pathway inhibitors for treatment of asthma

泛素通路抑制剂用于治疗哮喘

• 批准号: 8647389
• 负责人: Kumar Suresh
• 金额: $ 22.24万
• 依托单位: PROGENRA, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647389
• 关键词: Adrenal Cortex Hormones; Adult; Adverse effects; Affect; Agonist; Allergens; Allergic; Allergic Disease; Allergic inflammation; American; American Lung Association; Animal Model; Anti-Inflammatory Agents; Asthma; Atopic Dermatitis; Attenuated; Biological Assay; C2 Domain; CD4 Positive T Lymphocytes; Cell Count; Cell Line; Cells; Characteristics; Child; Chronic Disease; Cytokine Activation; Development; Digit structure; Disease; Environmental Risk Factor; Family; Fluorescence Resonance Energy Transfer; Genetic; Goals; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immune system; Inflammation; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Irrigation; Knockout Mice; Lead; Ligase; Liquid substance; Lung; Lung Inflammation; Measures; Mediating; Mediator of activation protein; Modeling; Monitor; Morbidity - disease rate; Mus; N-terminal; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phase; Prevalence; Preventive; Production; Proteins; Quality of life; Recruitment Activity; Respiratory Tract Infections; Serum; Sputum; Symptoms; T cell regulation; T-Lymphocyte; Technology; Therapeutic; Tissues; Ubiquitin; Work; adapter protein; airway hyperresponsiveness; airway inflammation; allergic response; base; chemokine; counterscreen; cytokine; enzyme pathway; eosinophil; high throughput screening; improved; inhibitor/antagonist; mimetics; mouse model; multicatalytic endopeptidase complex; neutrophil; novel; peripheral blood; preclinical evaluation; preclinical study; public health relevance; response; small molecule; small molecule libraries; therapeutic target; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Asthma is a chronic disease with considerable morbidity and no cures. Symptomatic treatment is efficacious but produces significant adverse effects. Thus, improved, targeted therapies for asthma are needed. Asthma develops when T cells (CD4+) differentiate to effector T cells, which secrete cytokines that assist in the recruitment and proliferation of various innate immune cells into tissues. Th2 and Th17 cells contribute to pathogenesis by secreting inflammatory cytokines that induce the influx of neutrophils and eosinophils, leading to airway inflammation. Targeted suppression of pro-inflammatory cytokines and chemokines are thus attractive approaches to attenuate allergic responses in asthma. It is proposed here to achieve this therapeutic aim by exploiting the ubiquitin proteasome pathway. Protein ubiquitylation is a key regulatory mechanism of innate and adaptive immune systems; ligases such as Itch, Nedd4 (HECT), Cbl-b, and MID1 (RING) regulate immune responses in asthma. Nedd4 ligases including Itch negatively regulate allergic immune responses. Notably, genetic disruption of Itch in mice or humans causes multi-system immune disorders and lung inflammation. Several Nedd4 family E3 ligases exist in an auto-inhibited state; Itch is kept inactive by the N-terminal auto-inhibitory C2 domain and is activated by adapter proteins such as the Nedd4- family interacting protein 1 (Ndfip1), which relieves the auto-inhibition. Ndfip1 promotes activity of multiple E3 ligases, thereby limiting both Th2 differentiation and IL-4/IL-5 /IL-13 production in T cells as well as the pathogenicity of Th17 cells, and Ndfip1-/- mice develop inflammation in the lungs characteristic of that induced by Th2 cytokine producing T cells. Moreover, SNPs in Ndfip1 are found associated with asthma and atopic dermatitis. Thus, Ndfip1 is a key negative modulator of T cell regulation and allergic inflammatory responses, and therapeutic mimetics of Ndfip1 should selectively activate ubiquitylation cascades to limit Th2 and Th17 cytokine production and thereby diminish allergic inflammation. Such mimetics will be identified in high throughput screening of small molecule libraries with the use of Progenra's E3 ligase assay technology adapted to identify activators of Itch. Cell proof of concept assays will measure the impact of selected small molecule agonists in Type 2 helper T cells and relevant allergy response models. In Phase II, lead optimization and additional preclinical studies will be performed with the best agonists to ascertain their ability o modulate Itch functions as well as to attenuate inflammation in relevant mouse models.

描述（由申请人提供）：哮喘是一种发病率相当高且无法治愈的慢性疾病。对症治疗有效，但会产生显着的副作用。因此，需要改进的、针对哮喘的靶向疗法。当 T 细胞 (CD4+) 分化为效应 T 细胞时，哮喘就会发生，效应 T 细胞会分泌细胞因子，帮助各种先天免疫细胞招募和增殖到组织中。 Th2 和 Th17 细胞通过分泌炎症细胞因子诱导中性粒细胞和嗜酸性粒细胞流入，从而导致气道炎症，从而促进发病。因此，有针对性地抑制促炎细胞因子和趋化因子是减轻哮喘过敏反应的有吸引力的方法。这里建议通过利用泛素蛋白酶体途径来实现这一治疗目标。蛋白质泛素化是先天性和适应性免疫系统的关键调节机制； Itch、Nedd4 (HECT)、Cbl-b 和 MID1 (RING) 等连接酶调节哮喘中的免疫反应。 Nedd4 连接酶（包括 Itch）负向调节过敏性免疫反应。值得注意的是，小鼠或人类瘙痒的基因破坏会导致多系统免疫紊乱和肺部炎症。几种 Nedd4 家族 E3 连接酶以自动抑制状态存在； N 端自动抑制 C2 结构域使痒保持不活跃状态并被激活 通过接头蛋白（如 Nedd4 家族相互作用蛋白 1 (Ndfip1)）来缓解自身抑制。 Ndfip1 促进多种 E3 连接酶的活性，从而限制 T 细胞中 Th2 分化和 IL-4/IL-5/IL-13 的产生以及 Th17 细胞的致病性，Ndfip1-/- 小鼠会出现肺部特征性炎症由产生 Th2 细胞因子的 T 细胞诱导的。此外，Ndfip1 中的 SNP 被发现与哮喘和特应性皮炎相关。因此，Ndfip1 是 T 细胞调节和过敏性炎症反应的关键负调节剂，Ndfip1 的治疗模拟物应选择性激活泛素化级联，以限制 Th2 和 Th17 细胞因子的产生，从而减少过敏性炎症。此类模拟物将通过使用适用于鉴定 Itch 激活剂的 Progenra 的 E3 连接酶测定技术，在小分子文库的高通量筛选中进行鉴定。细胞概念验证检测将测量所选小分子激动剂对 2 型辅助 T 细胞和相关过敏反应模型的影响。在第二阶段，将使用最好的激动剂进行先导优化和额外的临床前研究，以确定它们在相关小鼠模型中调节瘙痒功能以及减轻炎症的能力。