Immune responses to islet amyloid in beta-cell death

β细胞死亡中对胰岛淀粉样蛋白的免疫反应

• 批准号: 10265389
• 负责人: Andrew T. Templin
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265389
• 关键词: Address; Advisory Committees; Affect; Amyloid; Amyloid deposition; Antigens; Apoptosis; Award; Beta Cell; Blindness; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Death; Cell Death Signaling Process; Cell physiology; Cells; Cellular Structures; Cellular biology; Cessation of life; Characteristics; Data; Diabetes Mellitus; Disease; Exhibits; Functional disorder; General Population; Goals; Health Benefit; Healthcare Systems; Heart Diseases; Human; Immune; Immune response; Immune system; Immunologist; Immunology; In Vitro; Individual; Infiltration; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interleukin-1 beta; International; Investigation; Islets of Langerhans; K-Series Research Career Programs; Kidney Failure; Laboratories; Literature; Location; Lymphocyte; Lytic; MAPK8 gene; Mediating; Mentors; Messenger RNA; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Play; Positioning Attribute; Process; Production; Protein Kinase; Proteins; Publications; RIPK1 gene; Rag1 Mouse; Reporting; Research; Role; Secretory Cell; Signal Pathway; Signal Transduction; Stroke; T-Lymphocyte; TNF gene; TNFRSF1A gene; Testing; Time; Training; Transgenic Mice; Type 2 diabetic; United States Department of Veterans Affairs; Veterans; amyloid formation; base; career; career development; immunogenic; immunogenic cell death; in vivo; inhibitor/antagonist; islet; islet amyloid polypeptide; mRNA Expression; macrophage; military veteran; mixed lineage kinase 3; mouse model; novel; novel strategies; novel therapeutic intervention; preservation; prevent; recruit; response; sound

The applicant seeks a VA Career Development Award-2 (CDA-2) to further our understanding of the pathogenesis of β-cell loss in type 2 diabetes (T2D) and support his career development at the Veteran’s Affairs Puget Sound Health Care System (VAPSHCS). His expertise in cell and molecular biology, islet inflammation, and islet amyloid deposition, along with his strong mentors (Steven Kahn and Jane Buckner), collaborators (Andrew Oberst and Matthias von Herrath), Advisory Committee (Rebecca Hull, Jerry Palmer, Alvin Powers), and location at the VAPSHCS, make him uniquely qualified to execute the proposed studies. With the support of this award, he will investigate novel and underappreciated aspects of β-cell death in T2D, interact with internationally-recognized diabetologists and immunologists, and undertake didactic and laboratory-based immunology training. These activities will allow the candidate to author additional high impact publications, gain research independence, and position himself to successfully compete for a VA Merit Review Award. The scientific goals of this proposal are to define the roles of necroptosis (a novel form of cell death) and T cells in islet amyloid-induced β-cell loss in order to develop new treatments for individuals afflicted by T2D. Islet amyloid is a pathologic hallmark of T2D, where it elicits islet inflammation and β-cell death. Investigation of the mechanisms of amyloid-induced β-cell death have focused largely on apoptosis signaling. Preliminary data in this application show for the first time that a recently described alternative form of cell death signaling called necroptosis is activated by islet amyloid formation. These data also show that components of this cell death pathway, including receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL), are present in β cells. A central characteristic of necroptosis is its ability to elicit immune responses to cellular antigens that are released by this form of lytic cell death. Consistent with this process occurring in response to islet amyloid, preliminary data show that amyloid-laden islets exhibit significantly higher T cell abundance and mRNA expression. Based on these findings and the literature, I hypothesize that islet amyloid-induced TNFα production by macrophages leads to RIPK3-mediated β-cell necroptosis, which results in T lymphocyte recruitment to amyloid-laden islets and exacerbation of amyloid-induced β-cell dysfunction and death. To test this hypothesis, the following specific aims are proposed: Specific Aim 1: Determine the role of RIPK3 signaling in amyloid-induced β-cell death, β-cell dysfunction, and islet immune responses. The contribution of RIPK3 signaling to islet amyloid-induced β-cell death will be determined in vitro using 1) a RIPK3 inhibitor, and 2) islets from Ripk3-/- mice crossed with amyloid-prone human IAPP (hIAPP) transgenic mice. These Ripk3-/- x hIAPP mice will also be used to determine whether RIPK3 loss ameliorates amyloid-induced islet immune responses and β-cell death in vivo. Specific Aim 2: Determine the role of T lymphocytes in amyloid-induced β-cell death and dysfunction. Islet amyloid-prone mice lacking lymphocytes (Rag1-/- x hIAPP) will be used to determine the role of T cells in amyloid-induced β-cell death and dysfunction, and in amyloid deposition itself. The relationship between islet lymphocytes, amyloid deposition, inflammation, and β-cell death will be evaluated 1) in vitro using isolated islets, and 2) in vivo using this novel amyloid-prone, lymphocyte deficient mouse model. The relationship between islet amyloid deposition, immune cell abundance, and β-cell death will also be evaluated in human pancreas sections.

申请人希望获得VA职业发展奖-2 (CDA-2)，以进一步了解我们的专业