Intracellular Targeting of Proinflammatory Pathways to Ameliorate Type 1 Diabetes

细胞内靶向促炎途径改善 1 型糖尿病

• 批准号: 7615875
• 负责人: Daniel J. Moore
• 金额: $ 5.48万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-16 至 2011-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615875
• 关键词: Adaptor Signaling Protein; Adherence; Adult; Affect; American; Amputation; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Beta Cell; Biology; Blindness; Cell Nucleus; Cell surface; Cells; Cellular Immunology; Cessation of life; Characteristics; Child; Childhood; Chronic; Chronic Disease; Class; Clinical; Coma; Complement; Complex; Data; Dendritic Cells; Development; Diabetes Mellitus; Diabetes prevention; Disease; Disease remission; Distal; Event; Face; Faculty; Genetic; Immune; Immune Tolerance; Immunologics; Immunotherapy; Inbred NOD Mice; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-1 beta; Karyopherins; Kidney Failure; Knowledge; Laboratories; Lead; Life; Link; Mediating; Methods; Modeling; Morbidity - disease rate; Natural Immunity; Nuclear Import; Nuclear Translocation; Paint; Pathogenesis; Pathway interactions; Patients; Peptides; Play; Positioning Attribute; Predisposition; Prevention; Prevention strategy; Process; Proteins; Public Health; Recording of previous events; Research; Risk; Role; Seizures; Self Tolerance; Signal Pathway; Signal Transduction; Site; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TLR4 gene; Testing; Therapeutic; Time; Tissues; Toll-like receptors; Training; Translating; Transplantation; cell type; cellular transduction; chronic autoimmune disease; crosslink; cytokine; day; design; extracellular; human disease; inhibitor/antagonist; innovation; interferon gamma receptor; interferon gamma receptors; islet; macrophage; mortality; novel; pre-clinical; prevent; programs; protein activation; receptor; research study; transcription factor

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is a chronic autoimmune disease with high risk for long-term morbidity and mortality. Although insulin can provide a relatively normal life for the affected children and adults, the therapy poses risk for seizures, coma, and death and even compliant patients are not always protected from complications such as blindness, renal failure, and amputation. Our current understanding of the disease paints a complex picture in which nearly every immune cell is involved. These interactions include requisite contributions from T cells, B lymphocytes, dendritic cells, and macrophages. The activation of these cells results in a state of tissue inflammation and ultimate destruction of insulin-producing islet beta cells by proinflammatory cytokines and other noxious products of inflammation. To activate the transcriptional program associated with the inflammatory state, these deleterious signals must be transduced from the cell surface to the nucleus. This process requires the nuclear import of proinflammatory transcription factors and depends on the action of karyopherin/importin complexes. We have developed a cell-penetrating inhibitor of nuclear import which suppresses accelerated diabetes and insulitis for one year in NOD mice, the most widely used model of human disease. In this proposal, we will test the central hypothesis that targeting two key control points required for the inflammatory response will ameliorate and possibly reverse autoimmune diabetes. In aim 1, we will determine the efficacy of a nuclear import inhibitor in preventing or reversing spontaneous diabetes and will elucidate its mechanism of action. A second key step in inflammation is the activation of the mainstays of innate immunity, toll-like receptors (TLRs). These receptors have been implicated in diabetes pathogenesis and their activation can break immune tolerance. Signaling through these receptors depends on two key adaptor proteins, MyD88 and TRIP. In specific aim 2, we will develop cell-penetrating inhibitors of these pathways and test their efficacy in suppressing or reversing Type 1 diabetes. Overall, we will target both the proximal (adaptor protein activation) and distal (nuclear translocation) control points of proinflammatory signaling using innovative cell-penetrating peptides and proteins. Targeting these crucial intracellular signaling events represents a new strategy to ameliorate Type 1 diabetes. PUBLIC HEALTH RELEVANCE: Type 1 diabetes is a chronic illness that begins in childhood and afflicts more than 2 million Americans. Those affected face a life-time of injections without certainty that they will be protected from disease complications. We will test new pathways in T1D development and apply innovative approaches to target these pathways to reveal new strategies for prevention and reversal of this devastating illness.

描述（由申请人提供）：1 型糖尿病 (T1D) 是一种慢性自身免疫性疾病，具有高长期发病和死亡风险。尽管胰岛素可以为受影响的儿童和成人提供相对正常的生活，但该疗法存在癫痫、昏迷和死亡的风险，甚至顺从的患者也不一定能避免失明、肾衰竭和截肢等并发症。我们目前对这种疾病的理解描绘了一幅复杂的图景，几乎所有免疫细胞都参与其中。这些相互作用包括 T 细胞、B 淋巴细胞、树突状细胞和巨噬细胞的必要贡献。这些细胞的激活导致组织炎症状态，并最终被促炎细胞因子和其他炎症有害产物破坏产生胰岛素的胰岛β细胞。为了激活与炎症状态相关的转录程序，这些有害信号必须从细胞表面转导到细胞核。该过程需要促炎转录因子的核输入，并取决于核转运蛋白/输入蛋白复合物的作用。我们开发了一种细胞穿透核输入抑制剂，可在 NOD 小鼠（人类疾病最广泛使用的模型）中抑制加速糖尿病和胰岛素炎一年。在该提案中，我们将测试中心假设，即针对炎症反应所需的两个关键控制点将改善并可能逆转自身免疫性糖尿病。在目标 1 中，我们将确定核输入抑制剂在预防或逆转自发性糖尿病方面的功效，并阐明其作用机制。炎症的第二个关键步骤是激活先天免疫的支柱 Toll 样受体 (TLR)。这些受体与糖尿病发病机制有关，它们的激活可以破坏免疫耐受。通过这些受体的信号传导取决于两个关键的接头蛋白：MyD88 和 TRIP。在具体目标 2 中，我们将开发这些途径的细胞穿透抑制剂，并测试它们在抑制或逆转 1 型糖尿病方面的功效。总体而言，我们将使用创新的细胞穿透肽和蛋白质来靶向促炎信号传导的近端（接头蛋白激活）和远端（核易位）控制点。针对这些关键的细胞内信号传导事件代表了改善 1 型糖尿病的新策略。公共卫生相关性：1 型糖尿病是一种从儿童期开始的慢性疾病，困扰着超过 200 万美国人。受影响的人将面临一生的注射，但不确定他们是否会免受疾病并发症的影响。我们将测试 T1D 发展的新途径，并应用创新方法来针对这些途径，以揭示预防和逆转这种毁灭性疾病的新策略。