Genes And Gene Products As Immunoadjuvants

作为免疫佐剂的基因和基因产物

基本信息

批准号：
10928528
负责人：
Steven Holland
金额：
$ 108.65万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10928528
关键词：
Acquired Immunodeficiency Syndrome Adult Affect Bronchiectasis Child Coccidioidomycosis Cryptococcosis Cutaneous Cystic Fibrosis Cytokine Receptors Cytokine Signaling Defect Development Diagnosis Disease Disease Resistance Drug resistance Dysmyelopoietic Syndromes Epidemiology Epigenetic Process Epithelium Etiology Functional disorder Genes Genetic Genus Mycobacterium Granulomatous Granulomatous disease Histoplasmosis Host Defense Human IL17 gene Immune Immune response Immunity Immunobiology Immunocompromised Host Immunologic Adjuvants In Vitro Infection Inflammatory Innate Immune Response Interferon Type II Interleukin-12 Knowledge Lesion Lung Lung diseases Lymphocyte Macrophage Malignant Neoplasms Microbe Microbiology Mutation Mycobacterium Infections Mycoses Nature Organism Outcome Pathogenesis Pathway interactions Patients Phagocytes Predisposition Production Regulation Role Salmonella Sarcoidosis Signal Pathway Syndrome TNF gene Therapeutic Tuberculosis cytokine cytokine therapy drug-sensitive experimental study fungus gene product interest interleukin-23 microbial mycobacterial non-tuberculosis mycobacteria non-tuberculous mycobacterial infection novel therapeutic intervention participant enrollment pathogen response tuberculosis treatment

项目摘要

We are working on the identification, description, and treatment of congenital and acquired syndromes of increased susceptibility to mycobacterial and intracellular fungal infections, including coccidioidomycosis. The syndromes in which we are interested primarily affect the phagocytes, and are most apparent in the increased susceptibility to nontuberculous mycobacteria. These organisms are thought to be important pathogens only in the immunocompromised host. Therefore, we have sought to identify patients without previously recognized forms of immunocompromise who have these infections and then determine the nature of their susceptibility. In this way we have identified and characterized the pathways involved in the control of mycobacteria and other intracellular pathogens, such as Salmonella, histoplasmosis, coccidioidomycosis, and cryptococcosis as well as nontuberculous mycobacteria. The abnormalities we have already identified center around macrophage/lymphocyte interactions leading to the production of or response to interferon gamma, IL-12, IL-23, IL-17 and tumor necrosis factor. In addition, the pathways regulating the response to tumor necrosis factor overlap with the interferon gamma signaling pathways and have been shown to be lesioned in patients with these infections. The study of these "experiments of nature" highlights the critical role of the macrophage/ lymphocyte interaction in control of mycobacteria and other intracellular pathogens, including fungi. These observations have led us to explore cytokine therapies and cytokine modifying therapies that may have broader applications to the treatment of tuberculosis. Over the last year we have continued our focus on the importance of the regulation of inflammatory genes in mycobacterial infections through the study of patients with extrapulmonary fungi. We have identified abnormalities in cytokine receptors and signaling in those with histoplasmosis and coccidioidomycosis as well as mycobacteria. We have also focused on the syndrome of monocytopenia and mycobacterial disease (MonoMAC), which is due to mutations in GATA2 and also predisposes to myelodysplasia and malignancy. The identification of genes in these overlapping pathways has helped us understand the control of intracellular infection and should lead us to the development of more focused and more successful therapeutics. These infections overlap in many ways with those seen in AIDS. Using tis knowledge of the granulomatous response we are now enrolling patients with sarcoidosis to understand underlying causes of disease.

我们正在致力于识别、描述和治疗对分枝杆菌和细胞内真菌感染（包括球孢子菌病）易感性增加的先天性和获得性综合征。我们感兴趣的综合征主要影响吞噬细胞，最明显的是对非结核分枝杆菌的易感性增加。这些生物体被认为仅在免疫功能低下的宿主中才是重要的病原体。因此，我们试图识别出患有这些感染的先前未识别的免疫功能低下形式的患者，然后确定他们的易感性性质。通过这种方式，我们已经鉴定并表征了控制分枝杆菌和其他细胞内病原体（例如沙门氏菌、组织胞浆菌病、球孢子菌病和隐球菌病以及非结核分枝杆菌）的途径。我们已经发现的异常集中在巨噬细胞/淋巴细胞相互作用上，导致干扰素 γ、IL-12、IL-23、IL-17 和肿瘤坏死因子的产生或反应。此外，调节肿瘤坏死因子反应的途径与干扰素γ信号传导途径重叠，并且已被证明在这些感染的患者中受到损害。这些“自然实验”的研究强调了巨噬细胞/淋巴细胞相互作用在控制分枝杆菌和其他细胞内病原体（包括真菌）中的关键作用。这些观察结果促使我们探索细胞因子疗法和细胞因子修饰疗法，它们可能在结核病的治疗中具有更广泛的应用。去年，我们通过对肺外真菌患者的研究，继续关注分枝杆菌感染中炎症基因调节的重要性。我们已经发现组织胞浆菌病、球孢子菌病以及分枝杆菌患者的细胞因子受体和信号传导存在异常。我们还关注单核细胞减少症和分枝杆菌病 (MonoMAC) 综合征，该综合征是由 GATA2 突变引起的，也容易导致骨髓增生异常和恶性肿瘤。这些重叠途径中基因的识别帮助我们了解细胞内感染的控制，并应该引导我们开发更有针对性和更成功的治疗方法。这些感染在很多方面与艾滋病中的感染有重叠。利用肉芽肿反应的知识，我们现在正在招募结节病患者，以了解疾病的根本原因。

项目成果

期刊论文数量（56）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Polymorphisms associated with resistance and cross-resistance to aminoglycosides and capreomycin in Mycobacterium tuberculosis isolates from South Korean Patients with drug-resistant tuberculosis.

韩国耐药结核病患者分离出的结核分枝杆菌中与氨基糖苷类和卷曲霉素耐药性和交叉耐药性相关的多态性。

DOI：
发表时间：
2010-02
期刊：
影响因子：
9.4
作者：
Via, Laura E;Cho, Sang;Hwang, Soohee;Bang, Hyeeun;Park, Seung Kyu;Kang, Hyung Seok;Jeon, Doosoo;Min, Seon Yeong;Oh, Taegwon;Kim, Yeun;Kim, Young Mi;Rajan, Vignesh;Wong, Sharon Y;Shamputa, Isdore Chola;Carroll, Matthew;Goldfeder, Lisa;L
通讯作者：
L

Prevalence of nontuberculous mycobacterial lung disease in U.S. Medicare beneficiaries.

美国医疗保险受益人非结核分枝杆菌肺病的患病率。

DOI：
发表时间：
2012-04-15
期刊：
影响因子：
24.7
作者：
Adjemian, Jennifer;Olivier, Kenneth N;Seitz, Amy E;Holland, Steven M;Prevots, D Rebecca
通讯作者：
Prevots, D Rebecca

Recurrent Burkholderia gladioli suppurative lymphadenitis associated with neutralizing anti-IL-12p70 autoantibodies.

复发性伯克霍尔德杆菌唐菖蒲化脓性淋巴结炎与中和抗 IL-12p70 自身抗体相关。

DOI：
发表时间：
2013-08
期刊：
影响因子：
9.1
作者：
Sim, Bich;Browne, Sarah K;Vigliani, Marguerite;Zachary, Dalila;Rosen, Lindsey;Holland, Steven M;Opal, Steven M
通讯作者：
Opal, Steven M

B-cell lymphoma in a patient with complete interferon gamma receptor 1 deficiency.

干扰素 γ 受体 1 完全缺乏患者的 B 细胞淋巴瘤。

DOI：
发表时间：
2013-08
期刊：
影响因子：
9.1
作者：
Bax, Hannelore I;Freeman, Alexandra F;Anderson, Victoria L;Vesterhus, Per;Laerum, Dan;Pittaluga, Stefania;Wilson, Wyndham H;Holland, Steven M
通讯作者：
Holland, Steven M

Assessing the Collective Dynamics of Motile Cilia in Cultures of Human Airway Cells by Multiscale DDM.

通过多尺度 DDM 评估人气道细胞培养物中运动纤毛的集体动态。

DOI：
发表时间：
2017-07-11
期刊：
影响因子：
3.4
作者：
Feriani, Luigi;Juenet, Maya;Fowler, Cedar J;Bruot, Nicolas;Chioccioli, Maurizio;Holland, Steven M;Bryant, Clare E;Cicuta, Pietro
通讯作者：
Cicuta, Pietro