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Elucidating CD47-SHP1 biology to understand autoinflammatory disorders

阐明 CD47-SHP1 生物学以了解自身炎症性疾病

基本信息

批准号：
10084267
负责人：
Prajwal Gurung
金额：
$ 19.31万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084267
关键词：
Apoptosis Apoptotic Binding Biochemical Biology CASP3 gene CD47 gene Cell Death Cells Cessation of life Chimera organism Clinical Trials Data Development Disease Eating Embryo Etiology Genes Genetic Crosses Goals Health Human Human body Hyperactivity Immune Inflammation Inflammatory Integrins Interleukin-1 Interleukin-1 alpha Knockout Mice Knowledge Lead MAP3K7 gene Malignant Neoplasms Mediating Molecular Mus Mutation Myeloid Cells NR0B2 gene Outcome PTPN6 gene Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Phagocytes Pharmacotherapy Phosphoric Monoester Hydrolases Play Point Mutation Pregnancy Protein Tyrosine Phosphatase Proteins Pyoderma Gangrenosum RIPK1 gene Rare Diseases Research Role SYK gene Signal Transduction Skin Subcorneal Pustular Dermatosis Sweet&apos s Syndrome TNF gene Testing Therapeutic autoinflammation autoinflammatory base cancer therapy design insight mouse model neutrophil new therapeutic target novel novel therapeutic intervention novel therapeutics pup radioresistant rare condition side effect skin disorder skin lesion treatment strategy

项目摘要

ABSTRACT Neutrophilic dermatosis is a spectrum of skin disorders that include several rare diseases such as Sweet’s syndrome, pyoderma gangrenosum and subcorneal pustular dermatosis [1]. The treatment options for these rare diseases hallmarked by skin lesions filled with neutrophils are limited to the use of strong immunosuppressive, which are non-specific and have adverse side effects. Thus, specific novel therapeutic targets are much needed to help patients suffering from these disorders. Mice carrying a single point mutation in the Ptpn6 gene that results in a Y208N substitution in the Ptpn6 encoded SHP1 protein (known as Ptpn6spin mice), develop spontaneous footpad inflammation that mimics neutrophilic dermatosis. We have extensively studied Ptpn6spin mice and identified several novel therapeutic targets including IL-1 alpha, RIPK1, SYK and TAK1, that can be potentially beneficial to neutrophilic dermatosis patients [2]. Building upon these prior discoveries, we have set our goals to elucidate the role of an integrin-associated protein, CD47, and its crosstalk with SHP1 in regulating autoinflammatory disease and health. CD47 is ubiquitously expressed in the human body and provides a “don’t eat me” signal to the phagocytic cells [3, 4]. Our preliminary data show a crucial role for CD47 in regulating disease observed in Ptpn6spin mice; however, the cellular and molecular mechanisms remain unknown. Understanding the cellular and molecular basis of these pathologies will not only enhance our general understanding of CD47 and SHP1 biology, but also aid in the development of potential novel therapies for inflammation and cancer.

摘要嗜中性皮肤病是一系列皮肤病，包括几种罕见的疾病，如Sweet's 综合征、坏疽性脓皮病和角膜下脓疱性皮肤病[1]。这些罕见疾病的治疗选择以充满嗜中性粒细胞的皮肤损伤为特征的疾病限于使用强免疫抑制剂，其是非特异性的并且具有不良副作用。因此，非常需要特定的新治疗靶点来帮助患有这些疾病的患者。携带Ptpn 6基因单点突变的小鼠，导致Ptpn 6编码的SHP 1蛋白中的Y208 N取代（称为Ptpn 6spin小鼠），类似嗜中性皮肤病的自发性足垫炎症。我们广泛研究了Ptpn 6spin 小鼠，并确定了几个新的治疗靶点，包括IL-1 α，RIPK 1，SYK和TAK 1，可以对中性粒细胞皮肤病患者可能有益[2]。基于这些先前的发现，我们我们的目标是阐明整合素相关蛋白CD 47的作用及其与SHP 1的相互作用，自身炎症性疾病和健康。CD 47在人体中广泛表达，并提供了一种“不需要的”免疫抑制剂。吃我”信号的吞噬细胞[3，4]。我们的初步数据显示，CD 47在调节在Ptpn 6spin小鼠中观察到的疾病;然而，细胞和分子机制仍然未知。了解这些病理的细胞和分子基础不仅可以提高我们的总体认识，了解CD 47和SHP 1生物学，还有助于开发潜在的新疗法，炎症和癌症。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CD47 halts Ptpn6-deficient neutrophils from provoking lethal inflammation.

DOI：
10.1126/sciadv.ade3942
发表时间：
2023-01-06
期刊：
SCIENCE ADVANCES
影响因子：
13.6
作者：
Mazgaeen, Lalita;Yorek, Matthew;Saini, Saurabh;Vogel, Peter;Meyerholz, David K.;Kanneganti, Thirumala-Devi;Gurung, Prajwal
通讯作者：
Gurung, Prajwal

Reconciling protective and pathogenic roles of the NLRP3 inflammasome in leishmaniasis.