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: 7920109
• 负责人: Daniel J. Moore
• 金额: $ 4.04万
• 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 2011-05-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920109
• 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; 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; 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; design; extracellular; high risk; human disease; inhibitor/antagonist; innovation; interferon gamma receptor; interferon gamma receptors; islet; macrophage; mortality; novel; pre-clinical; prevent; programs; protein activation; public health relevance; 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，长期发病率和死亡率很高。尽管胰岛素可以为受影响的儿童和成人提供相对正常的寿命，但该疗法对癫痫发作，昏迷和死亡构成了风险，甚至并不总是受到保护，并不总是保护诸如失明，肾衰竭和截肢之类的并发症。我们目前对疾病的理解描绘了一幅复杂的图画，其中几乎每个免疫细胞都涉及。这些相互作用包括来自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的状态和通过促炎性细胞因子和其他有害炎症产物对产生胰岛素的胰岛β细胞的最终破坏。为了激活与炎症状态相关的转录程序，必须将这些有害信号从细胞表面转到细胞核。该过程需要促炎性转录因子的核导入，并取决于核蛋白/导入蛋白复合物的作用。我们已经开发了一种细胞渗透核进口抑制剂，该抑制剂在NOD小鼠中抑制了一年的加速糖尿病和胰岛炎，这是最广泛使用的人类疾病模型。在此提案中，我们将检验以下中心假设，即针对炎症反应所需的两个关键控制点将改善自身免疫性糖尿病。在AIM 1中，我们将确定核进口抑制剂在预防或逆转自发糖尿病方面的功效，并阐明其作用机理。炎症的第二个关键步骤是激活先天免疫力，Toll样受体（TLRS）。这些受体与糖尿病的发病机理有关，它们的激活可以破坏免疫耐受性。通过这些受体的信号传导取决于两个关键的衔接蛋白MyD88和Trip。在特定的目标2中，我们将开发这些途径的细胞渗透抑制剂，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培养肽和蛋白质靶向促炎信号传导的近端（衔接蛋白激活）和远端（核转运）控制点。针对这些至关重要的细胞内信号事件是改善1型糖尿病的新策略。公共卫生相关性：1型糖尿病是一种慢性疾病，始于童年时期，折磨超过200万美国人。受影响的人面临着一生的注射时间，毫无疑问，它们会受到疾病并发症的保护。我们将测试T1D开发中的新途径，并采用创新的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。

项目成果

Mitigating micro-and macro-vascular complications of diabetes beginning in adolescence.

减轻从青春期开始的糖尿病的微血管和大血管并发症。

• DOI: 10.2147/vhrm.s4891
• 发表时间: 2009
• 期刊: Vascular health and risk management
• 影响因子: 2.9
• 作者: Moore,DanielJ;Gregory,JustinM;Kumah-Crystal,YaaA;Simmons,JillH
• 通讯作者: Simmons,JillH

Factors that influence parental attitudes toward enrollment in type 1 diabetes trials.

• DOI: 10.1371/journal.pone.0044341
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Buscariollo DL;Davidson MA;Black M;Russell WE;Rothman RL;Moore DJ
• 通讯作者: Moore DJ

Autoimmune alternating hypo- and hyperthyroidism in children.

儿童自身免疫性甲状腺功能减退症和甲状腺功能亢进症交替出现。

• DOI: 10.1177/0009922811412583
• 发表时间: 2011
• 期刊: Clinical pediatrics
• 影响因子: 1.6
• 作者: Mathew,ReviP;Moore,DanielJ
• 通讯作者: Moore,DanielJ

Accounting for chance in the calculus of autoimmune disease.

考虑自身免疫性疾病的计算中的机会。

• DOI: 10.1016/j.mehy.2009.09.009
• 发表时间: 2010
• 期刊: Medical hypotheses
• 影响因子: 4.7
• 作者: Moore,DanielJ

Can technological solutions for diabetes replace islet cell function?

糖尿病的技术解决方案可以替代胰岛细胞功能吗？

• DOI: 10.4161/org.7.1.14028
• 发表时间: 2011
• 期刊: Organogenesis
• 影响因子: 2.3
• 作者: Gregory,JustinM;Moore,DanielJ
• 通讯作者: Moore,DanielJ