Regulation of Autoimmune Type 1 Diabetes by Serpins B1 and A1 (Alpha 1-Antitrypsin)

Serpins B1 和 A1（α 1-抗胰蛋白酶）对自身免疫性 1 型糖尿病的调节

基本信息

批准号：
9556000
负责人：
ROHIT N. KULKARNI
金额：
$ 21.84万
依托单位：
SERPLUS TECHNOLOGY, LLC
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-17 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9556000
关键词：
Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Antibody titer measurement Apoptotic Atlases Autoimmune Diseases Autoimmune Process Autoimmune Responses B Cell Proliferation Beta Cell Biological Biological Products Blood Glucose Cell physiology Cells Cellular Immunity Cellular biology Clinical Clinical Research Clinical Trials Combined Modality Therapy Complement Coupled Data Diabetes Mellitus Disease Duct (organ) structure Ductal Ductal Epithelial Cell Economic Burden Elastases Environmental Risk Factor Epithelium Financial compensation Future Genetic Glycosylated hemoglobin A Growth Health Health Care Costs Health Expenditures Human Hyperglycemia Immune response In Vitro Inbred NOD Mice Inflammation Inflammatory Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Interleukin-1 beta Islet Cell Islets of Langerhans Laboratories Life Liver Mediating Medical Methods Monitor Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Outcome Study Pancreas Pancreatic duct Patient-Focused Outcomes Patients Peptide Hydrolases Phase Plasma Plasma Proteins Preclinical Testing Process Production Property Proteins Publishing Quality of life Recombinant Proteins Recombinants Regulation Replacement Therapy Research Serine Proteinase Inhibitors Serpins Signal Pathway Structure of beta Cell of islet T-Lymphocyte Technology Testing Therapeutic Effect Tissues Toxicology Translating Transplantation Work alpha 1-Antitrypsin base burden of illness clinical candidate clinically relevant cytokine design disorder control early childhood effective therapy efficacy study elastase inhibitor experience global health immunogenicity immunoregulation improved in vivo in vivo Model insulin dependent diabetes mellitus onset islet islet allograft islet cell antibody mortality mouse model novel pre-clinical preservation prevent research clinical testing response skills treatment effect

项目摘要

The number of people with diabetes worldwide is predicted to increase from 415 million in 2015 to 642 million in 2040. The health care costs of treating the disease account for 12% of the global health expenditure and continue to be a huge economic burden (IDF World Atlas 2015). Type 1 diabetes mellitus (T1DM) constitutes 10-15% of the disease burden. It is an autoimmune disease, thought to be triggered by genetic or environmental factors in early childhood, which results in antibody- mediated destruction of insulin producing pancreatic β-cells causing life-threatening hyperglycemia. In contrast, type 2 diabetes mellitus (T2DM) develops later in life and results from insulin resistance in target tissues and inflammation coupled with an inadequate compensation by the β-cells. A major limitation in effectively treating both forms of the disease is preventing a decline in β- cell function and/or mass. Recently, the Kulkarni lab identified Serpin B1 (an intracellular SERine Proteinase Inhibitor) as a liver-derived protein factor that promotes a compensatory β-cell response by inhibiting elastase and inducing β-cell proliferation in multiple species by activating growth/survival factor signaling pathways. The structurally and functionally related human plasma protein alpha 1- antitrypsin (AAT, serpin A1) is in late stage clinical trials to delay the onset of T1DM after a majority of independent studies showed it could restore euglycemia in animal models of T1DM by preserving functional β-cells, enhancing islet allograft survival and modulating cellular immunity. Early stage clinical study results indicate that AAT reduces HbA1c levels and anti-islet cell antibody titers. Serpin B1 (sB1), like AAT, is an effective anti-inflammatory elastase inhibitor but unlike AAT, also induces β-cell proliferation, promotes insulin + cells in pancreatic ductal lining epithelia, inhibits NETosis (another pro-inflammatory process involved in diabetes) and regulates the expansion of Th17 cytokine producing cells in vitro. We therefore propose that sB1 may also work in vivo, either alone or in combination with AAT, to provide superior therapeutic effects in animal models of T1DM. We will test if sB1 -/+ AAT can more effectively prevent the onset of, or treat established, T1DM in the NOD mouse model by inducing proliferation of functional β-cells, enhancing production of insulin by ductal lining cells and protecting β-cells from the immune response. If successful, we will further develop this technology through preclinical and clinical testing with the intent to improve long-term outcome for patients with T1DM. The proposed research in phase I will focus on (Aim 1) producing highly purified active recombinant proteins and (Aim 2) providing proof-of-principle in animal models of T1DM. The outcome of these studies will guide the design of future efficacy studies in animals and humans.

预计全球糖尿病的人数将从2015年的4.15亿增加到2040年的6.42亿。治疗该疾病的医疗保健费用占全球健康支出的12％，并继续是巨大的经济伯恩（IDF World Atlas 2015）。 1型糖尿病（T1DM）占伯宁疾病的10-15％。这是一种自身免疫性疾病，被认为是由儿童早期遗传或环境因素引起的，这导致抗体介导的胰岛素产生胰腺产生胰腺β细胞的破坏，从而导致威胁生命的高血糖。相比之下，2型糖尿病（T2DM）在生命后期发展，并且靶向时机中的胰岛素抵抗和炎症以及β细胞补偿不足的结果。有效治疗两种形式的疾病的主要局限性是防止β细胞功能和/或质量的下降。最近，库尔卡尼实验室（Kulkarni Lab）将SERPIN B1（一种细胞内丝氨酸蛋白酶抑制剂）鉴定为肝衍生的蛋白质因子，通过激活生长/存活因子信号传导途径，通过抑制弹性酶和在多种物种中诱导的β-细胞增殖来促进补偿性β细胞反应。 The structurally and functionally related human plasma protein alpha 1- antitrypsin (AAT, serpin A1) is in late stage clinical trials to delay The onset of T1DM after a majority of independent studies shown it could restore euglycemia in animal models of T1DM by preserving functional β-cells, enhancing islet allograft survival and modulating cellular immunohistors.早期临床研究结果表明，AAT降低了HBA1C水平和抗ISLET细胞抗体滴度。 SERPIN B1（SB1）与AAT一样，是一种有效的抗炎弹性酶抑制剂，但与AAT不同，也诱导β细胞增殖，促进胰腺导管衬里上皮细胞中的胰岛素 +细胞，抑制Netosis（另一个涉及糖尿病的促炎过程）（糖尿病的另一种促进症），并构成了Thet cent cytrok int cent cytrok int cytror int cyt of th17。因此，我们建议SB1也可以单独或与AAT结合在体内工作，以在T1DM动物模型中提供出色的治疗作用。我们将通过诱导功能性β细胞的增殖来测试SB1 - /+ AAT是否可以更有效地防止NOD小鼠模型中建立的T1DM的发作或治疗已建立的T1DM，从而通过导管衬里细胞增强胰岛素的产生并保护β细胞免受免疫源性的影响。如果成功，我们将通过临床前和临床测试进一步开发这项技术，目的是改善T1DM患者的长期结局。第一阶段的拟议研究将重点放在（AIM 1）产生高度纯化的活性重组蛋白，并（AIM 2）在T1DM动物模型中提供原则证明。这些研究的结果将指导动物和人类未来效率研究的设计。