Heritable Autoimmune and Neurodegenerative Disorders

遗传性自身免疫性疾病和神经退行性疾病

• 批准号: 6811647
• 负责人: ANIL B MUKHERJEE
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 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/6811647
• 关键词: IgA nephropathy; amidohydrolases; asthma; children; cysteamine; developmental genetics; disease /disorder model; embryonic stem cell; functional /structural genomics; gene expression; gene mutation; genetic regulation; glycoproteins; human subject; laboratory mouse; neuronal ceroid lipofuscinosis; phospholipase A2; prostaglandin endoperoxide synthase; prostaglandin receptor; transfection

The Section on Developmental Genetics conducts both basic and clinical investigations to understand molecular mechanisms of inflammatory/autoimmune and neurodegenerative diseases and to develop novel approaches for the treatment of these diseases. Towards these goals our studies are focused on understanding the regulation and physiological functions of several genes and their products. These include uteroglobin (UG), soluble phospholipases A2 (sPLA2s), palmitoyl-protein thioesterase (PPT) and neutral ceramidase. UG is a multifunctional secreted protein with potent sPLA2 inhibitory and immunomodulatory activities. By generating UG-deficient mice we demonstrated that these animals suffer from IgA-nephropathy, the most common primary renal glomerular disease for which there is no effective treatment. Thus, one of our goals is to understand the molecular mechanisms of this disease using our animal model and to develop novel therapeutic approaches. While studying the relationship between UG and sPLA2 , we serendipitously isolated another gene encoding palmitoyl-protein thioesterase (PPT) and found that inactivating mutations in this gene leads to infantile neuronal ceroid lipofuscinosis (INCL), the most severe form of childhood Batten disease that has no effective treatment. Currently, we are conducting a pilot study to determine whether Cystagon may be effective treatment for INCL. While the clinical investigations are ongoing, we have returned to the bench to understand the molecular mechanisms of this disease in further detail using a mouse model of INCL and to develop novel therapeutic approaches using gene transfer and embryonic stem (ES) cell technologies. During the past year we have accomplished the following: (a)Novel Role of Uteroglobin as a Repressor of PGD2 Receptor-Mediated COX-2 Gene Expression: Implications for Allergic Asthma; (b)Prostaglandin F2a receptor (FP)-mediated activation of NF-kB and COX-2 gene expression is inhibited by uteroglobin; (c)Uteroglobin-knockout mice are predisposed to lung tumorigenesis when exposed to NNK commonly present in cigarette smoke; (d)In a piglet model of neonatal respiratory distress syndrome, it has been demonstrated intratracheal administration of recombinant uteroglobin (rUG) reduces inflammatory markers and no significant toxicity was noted raising the possibility that rUG may represent a promising therapy for the prevention of lung injury in preterm infants with RDS; (e)Interfeon-g (IFN-g) Stimulates the Expression of a Novel Secretoglobin Gene in Lymphoblasts; (f)cortical degeneration in PPT-KO mice could be determined by MRI paving the way for assessing the outcome of various treatment modalities using this animal model; (g)the preliminary results of the ongoing pilot study to determine if cystagon is beneficial for the treatment of infantile neuronal ceroid lipofuscinosis indicate that some parameters of this disease are stable and/or slightly improved by this treatment; (h)neutral ceramidase is part of a novel homeostatic mechanism to prevent apoptosis in vital organs such as the gastrointestinal tract and the kidneys.

发育遗传学科进行基础和临床研究，以了解炎症/自身免疫和神经退行性疾病的分子机制，并开发治疗这些疾病的新方法。为了实现这些目标，我们的研究重点是了解几种基因及其产物的调节和生理功能。这些包括子宫珠蛋白 (UG)、可溶性磷脂酶 A2 (sPLA2s)、棕榈酰蛋白硫酯酶 (PPT) 和中性神经酰胺酶。 UG 是一种多功能分泌蛋白，具有有效的 sPLA2 抑制和免疫调节活性。通过培育 UG 缺陷小鼠，我们证明这些动物患有 IgA 肾病，这是最常见的原发性肾小球疾病，目前尚无有效治疗方法。因此，我们的目标之一是利用我们的动物模型了解这种疾病的分子机制并开发新的治疗方法。在研究 UG 和 sPLA2 之间的关系时，我们偶然分离到了另一个编码棕榈酰蛋白硫酯酶 (PPT) 的基因，并发现该基因的失活突变会导致婴儿神经元蜡质脂褐质沉着症 (INCL)，这是儿童巴顿病最严重的一种形式。没有有效的治疗方法。目前，我们正在进行一项试点研究，以确定 Cystagon 是否可以有效治疗 INCL。在临床研究正在进行的同时，我们又回到了实验室，利用 INCL 小鼠模型进一步详细了解这种疾病的分子机制，并利用基因转移和胚胎干 (ES) 细胞技术开发新的治疗方法。在过去的一年里，我们完成了以下工作： (a) 子宫珠蛋白作为 PGD2 受体介导的 COX-2 基因表达抑制剂的新作用：对过敏性哮喘的影响； (b)前列腺素F2a受体(FP)介导的NF-kB激活和COX-2基因表达被子宫珠蛋白抑制； (c)子宫珠蛋白敲除小鼠在接触香烟烟雾中常见的 NNK 时容易发生肺部肿瘤； (d)在新生儿呼吸窘迫综合征的仔猪模型中，已证明气管内施用重组子宫珠蛋白（rUG）可减少炎症标志物，并且没有发现明显的毒性，这增加了rUG可能代表一种有前途的预防肺损伤疗法的可能性患有 RDS 的早产儿； (e) 干扰素-g (IFN-g) 刺激淋巴细胞中新型分泌球蛋白基因的表达； (f) PPT-KO小鼠的皮质变性可以通过MRI确定，为使用该动物模型评估各种治疗方式的结果铺平道路； (g) 正在进行的初步研究的初步结果表明，这种疾病的一些参数是稳定的和/或通过这种治疗略有改善； (h)中性神经酰胺酶是一种新型稳态机制的一部分，可防止胃肠道和肾脏等重要器官的细胞凋亡。