Role of NGF in inflammatory and proliferative cascades of psoriatic disease

NGF 在银屑病炎症和增殖级联反应中的作用

• 批准号: 7689638
• 负责人: SIBA P RAYCHAUDHURI
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689638
• 关键词: Affinity; American; Anesthesia procedures; Animal Experiments; Ankle; Antibodies; Apoptosis; Apoptotic; Arthritis; Asthma; Atopic Dermatitis; Autoimmune Process; Autologous; Blood; Blood Cells; Body part; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Culture Techniques; Cell Line; Cells; Cellular biology; Characteristics; Chemicals; Chronic; Clinical; Cutaneous; Cutaneous Involvement; Data; Degenerative polyarthritis; Dimensions; Discipline; Disease; Embryo; Endothelial Cells; Epidermis; Etiology; Event; Eye; Fibroblasts; Functional disorder; Gastrointestinal tract structure; Goals; Hand; Homing; Human; Human body; Immune; Immune system; In Situ Hybridization; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Intralesional Injections; Joints; K 252a; Knee; Language; Lesion; Leucocytic infiltrate; Life; Liquid substance; Lymphocyte Subset; Maintenance; Medicine; Modeling; Morbidity - disease rate; Mus; Musculoskeletal System; NF-kappa B; Nerve; Nerve Growth Factors; Neurogenic Inflammation; Neuropeptides; Neurotrophic Tyrosine Kinase Receptor Type 1; Organ; Pain; Pathogenesis; Pathologic; Patient Care; Patients; Peripheral Blood Mononuclear Cell; Pilot Projects; Play; Population; Process; Psoriasis; Psoriatic Arthritis; Reaction; Research; Research Personnel; Research Project Grants; Residual state; Rheumatoid Arthritis; Role; SCID Mice; Signal Transduction; Site; Skin; Skin Transplantation; Skin graft; Social Impacts; Source; Synovial Cell; Synovial Fluid; Synovial Membrane; System; T memory cell; T-Cell Activation; T-Lymphocyte; Tail; Tissues; Transplantation; Tropism; Up-Regulation; Veins; Vertebral column; Work; Wrist; Xenograft Model; Xenograft procedure; angiogenesis; chemokine; cytokine; economic impact; foot; improved; in vivo; inhibitor/antagonist; intradermal injection; intravenous injection; joint injury; keratinocyte; neutralizing antibody; neutrophil; novel therapeutic intervention; patient population; public health relevance; receptor; research study; skin disorder; skin xenograft; success; trafficking; transcriptional coactivator p75

DESCRIPTION (provided by applicant): The main objective of this study is to provide the direct and indirect evidences for the role of nerve growth factor (NGF) and its receptor system (NGF-R) in the pathogenesis of psoriasis and psoriatic arthritis (PsA). A role of neurogenic inflammation in psoriasis is suggested by proliferation of lesional cutaneous nerves, upregulation of neuropeptides, and clearance of psoriasis at the sites of anesthesia. Psoriatic keratinocytes (KC) express high level of NGF/NGF-R and NGF is mitogeic to KC. In the SCID mouse-psoriasis model, NGF antibody and K252a (NGF-R/TrkA inhibitor) improve psoriasis. Our preliminary data indicate that compared to rheumatoid arthritis (RA) and osteoarthritis (OA), the synovium of PsA is rich in NGF; major source of NGF is FLS; TrkA is upregulated in FLS, endothelial cells and activated T cells; NGF regulates both activation and survival of CD4+/CD8+ T cells. Thus, similar to psoriatic plaque, NGF/NGF-R may play a contributing role in the pathogenesis of PsA. To substantiate a direct regulatory role of NGF/NGF-R in psoriatic disease we will investigate whether injection of NGF and NGF activated autologus T lymphocytes induce psoriasis in nonlesional skin transplant in the SCID mouse-human skin xenograft model. NGF alone (n=15) and NGF activated autologous CD4+ (n=15) and CD8+ (n=15) T cells will be injected intradermally into the nonlesional psoriatic grafts. In the second group NGF activated CD4+ (n=15) and CD8+ (n=15) cells will be injected intravenously in the tail vein. Controls will be nonlesional psoriasis skin xenografts injected intradermally with unactivated autologous CD4+ (n=10) and CD8+ (n=10) T cells. Another set of controls will be skin grafts from healthy subjects injected with NGF activated autologous CD4+ (n=10) and CD8+ (n=10) T cells. Induction of psoriasis will be confirmed by identifying clinical, histopathological and immunological characteristics of psoriatic lesion. Blood, synovial fluid (SF) and synovial tissues of PsA (n=25) and controls [OA (n=20) and RA (n=10)] will also be examined to identify an immunoregulatory role of NGF/NGF-R on PBMC and SF derived activated memory T cells. The effect of NGF/NGF-R on activation, survival and homing of T cell will be assessed by Hi-D FACS analyses. The regulatory role of NGF on synovial tissue pathophysiology will be elucidated by examining the effect of NGF/NGF-R on proliferation and apoptosis of FLS. RELEVANCE TO VA PATIENT POPULATION: Psoriatic disease is a major morbidity among the VA patient population with profound social and economic impacts. The goal of this study is to understand the pathogenesis of psoriatic disease with an aim to develop better patient care. This study may provide a platform to develop novel therapeutic approach for psoriatic disease by targeting NGF/NGF-R system. PUBLIC HEALTH RELEVANCE: Psoriasis is a disease with flakey skin, and can be associated with arthritis of joints of hands, wrist, feet, ankle, knee, and spine. Nearly 2% of American population has psoriasis and 8-10% of psoriasis patients develop psoriatic arthritis. Psoriasis and psoriatic arthritis are life long chronic debilitating disease. A large number of the VA patient population suffers from these diseases. Cause of psoriatic arthritis is not known, treatment options for psoriatic arthritis are limited and worldwide only a few investigators are doing research to understand the disease process of psoriatic arthritis. In this proposed research project we will be investigating the role of nerve growth factor (NGF) in the disease process of psoriasis and psoriatic arthritis. NGF is a chemical mainly helps in to grow nerves in the embryo. NGF also irritates skin and other human body parts; in scientific language this is called inflammation. NGF is produced by skin cells and joint cells (synovial cells) and many other cells. NGF has a contributing role in several diseases including psoriasis. In this study we are doing a very important research work to find out how NGF causes psoriasis, induces inflammation and pain in psoriatic arthritis. Here we will transplant uninvolved skin from psoriasis patients and skin of normal healthy subjects to immune deficient mouse. We will collect blood cells from psoriasis patients and healthy subjects; we will treat these blood cells with NGF. These NGF treated cells will be injected into the transplanted human skin on mice. We expect that the injection of NGF treated blood cells from psoriasis patients will create psoriasis only in the mice transplanted with skin from psoriasis patients. Thus these experiments may help us to understand whether blood cells and NGF are responsible for causing psoriasis. Currently we are determining whether joint tissues from psoriatic arthritis has increased level of NGF and whether NGF is damaging the joint by altering the immune system. To determine these goals we are studying blood, joint fluid and joint tissues from patients with psoriatic arthritis and other forms of arthritis such as rheumatoid arthritis and osteoarthritis. Our initial results suggest that joint fluid of psoriatic arthritis has more NGF compared to rheumatoid arthritis and osteoarthritis. We have also noticed that NGF is likely activating a special group of immune cells (T lymphocytes) in the joint. It is possible that increased level of NGF and the hyperactive T cells have a contributing role to cause the joint inflammation. In a very recent animal experiment we have demonstrated that psoriasis can be treated by medicines which can neutralize the inflammatory effect of NGF. It is possible to develop nontoxic and effective medicines by neutralizing the bad effects of NGF. Our research work will help to understand the cause of psoriatic disease and thus to develop better patient care and treatment of psoriasis and arthritis. The success of this project will help the VA patient population immensely because both psoriasis and arthritis related sickness is a major problem among this group of patients.

描述（由申请人提供）： 本研究的主要目的是为神经生长因子（NGF）及其受体系统（NGF-R）在银屑病和银屑病关节炎（PsA）发病机制中的作用提供直接和间接证据。 病变皮神经的增殖、神经肽的上调以及麻醉部位银屑病的清除表明神经源性炎症在银屑病中的作用。银屑病角质形成细胞 (KC) 表达高水平的 NGF/NGF-R，并且 NGF 对 KC 有丝分裂作用。在 SCID 小鼠银屑病模型中，NGF 抗体和 K252a（NGF-R/TrkA 抑制剂）可改善银屑病。我们的初步数据表明，与类风湿性关节炎（RA）和骨关节炎（OA）相比，PsA的滑膜富含NGF； NGF的主要来源是FLS； TrkA 在 FLS、内皮细胞和活化 T 细胞中表达上调； NGF 调节 CD4+/CD8+ T 细胞的激活和存活。因此，与银屑病斑块类似，NGF/NGF-R 可能在 PsA 的发病机制中发挥重要作用。 为了证实 NGF/NGF-R 在银屑病疾病中的直接调节作用，我们将研究在 SCID 小鼠-人皮肤异种移植模型中的非病变皮肤移植中注射 NGF 和 NGF 激活的自体 T 淋巴细胞是否会诱导银屑病。单独的 NGF (n=15) 和 NGF 激活的自体 CD4+ (n=15) 和 CD8+ (n=15) T 细胞将皮内注射到非病变银屑病移植物中。在第二组中，NGF 激活的 CD4+ (n=15) 和 CD8+ (n=15) 细胞将被静脉注射到尾静脉中。对照是皮内注射未激活的自体 CD4+ (n=10) 和 CD8+ (n=10) T 细胞的非病变银屑病皮肤异种移植物。另一组对照是健康受试者的皮肤移植物，注射了 NGF 激活的自体 CD4+ (n=10) 和 CD8+ (n=10) T 细胞。通过鉴定银屑病病变的临床、组织病理学和免疫学特征来确认银屑病的诱发。 还将检查 PsA (n=25) 和对照 [OA (n=20) 和 RA (n=10)] 的血液、滑液 (SF) 和滑膜组织，以确定 NGF/NGF-R 对PBMC 和 SF 衍生的激活记忆 T 细胞。 NGF/NGF-R 对 T 细胞激活、存活和归巢的影响将通过 Hi-D FACS 分析进行评估。通过检查 NGF/NGF-R 对 FLS 增殖和凋亡的影响，阐明 NGF 对滑膜组织病理生理学的调节作用。 与 VA 患者群体的相关性：银屑病是 VA 患者群体中的一种主要疾病，具有深远的社会和经济影响。本研究的目的是了解银屑病的发病机制，以期提供更好的患者护理。这项研究可能为开发针对NGF/NGF-R系统的银屑病新治疗方法提供平台。 公共卫生相关性： 牛皮癣是一种皮肤鳞片状疾病，可能与手、腕、足、踝、膝和脊柱关节关节炎有关。近 2% 的美国人患有银屑病，8-10% 的银屑病患者会发展为银屑病关节炎。牛皮癣和牛皮癣关节炎是终生慢性衰弱性疾病。大量 VA 患者患有这些疾病。银屑病关节炎的病因尚不清楚，银屑病关节炎的治疗选择有限，全世界只有少数研究人员正在进行研究以了解银屑病关节炎的疾病过程。在这个拟议的研究项目中，我们将研究神经生长因子（NGF）在银屑病和银屑病关节炎疾病过程中的作用。 NGF是一种主要帮助胚胎神经生长的化学物质。 NGF还会刺激皮肤和其他人体部位；用科学语言来说，这称为炎症。 NGF由皮肤细胞和关节细胞（滑膜细胞）和许多其他细胞产生。 NGF 在包括牛皮癣在内的多种疾病中发挥着重要作用。在这项研究中，我们正在进行一项非常重要的研究工作，以了解 NGF 如何引起银屑病、诱发银屑病关节炎的炎症和疼痛。在这里，我们将把牛皮癣患者未受累的皮肤和正常健康受试者的皮肤移植到免疫缺陷小鼠身上。我们将从牛皮癣患者和健康受试者身上采集血细胞；我们将用 NGF 处理这些血细胞。这些经过 NGF 处理的细胞将被注射到小鼠移植的人类皮肤中。我们预计，注射经 NGF 处理的牛皮癣患者血细胞只会在移植牛皮癣患者皮肤的小鼠中产生牛皮癣。因此，这些实验可能有助于我们了解血细胞和 NGF 是否是导致牛皮癣的原因。目前，我们正在确定银屑病关节炎的关节组织中 NGF 水平是否升高，以及 NGF 是否通过改变免疫系统来损害关节。为了确定这些目标，我们正在研究银屑病关节炎和其他形式的关节炎（例如类风湿性关节炎和骨关节炎）患者的血液、关节液和关节组织。我们的初步结果表明，与类风湿关节炎和骨关节炎相比，银屑病关节炎的关节液中含有更多的 NGF。我们还注意到，NGF 可能会激活关节中一组特殊的免疫细胞（T 淋巴细胞）。 NGF 水平的增加和过度活跃的 T 细胞可能在引起关节炎症中发挥着重要作用。在最近的一项动物实验中，我们证明可以通过中和 NGF 炎症作用的药物来治疗牛皮癣。通过中和NGF的不良影响，有可能开发出无毒且有效的药物。我们的研究工作将有助于了解银屑病的病因，从而更好地治疗银屑病和关节炎的患者。该项目的成功将极大地帮助退伍军人管理局患者群体，因为牛皮癣和关节炎相关疾病都是该群体患者的主要问题。