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Enhanced pancreatic islet cell engraftment by treatment with serpin B1

丝氨酸蛋白酶抑制剂 B1 处理增强胰岛细胞植入

基本信息

批准号：
10383270
负责人：
ROHIT N. KULKARNI
金额：
$ 24.63万
依托单位：
SERPLUS TECHNOLOGY, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383270
关键词：
Acetylcysteine Adoption Animal Model Animals Anti-Inflammatory Agents Apoptosis Apoptotic Atlases Autoimmune Diseases B Cell Proliferation Beta Cell Biological Biology Blood Blood Glucose Businesses Cell Survival Cell Transplantation Cell physiology Cells Cellular biology Clinical Clinical Trials Cysteine Data Diabetes Mellitus Elastases Engraftment Environmental Risk Factor Epithelial Formulation Future Genetic Graft Rejection Growth Harvest Health Care Costs Health Expenditures Human Hyperglycemia Immune Immune Tolerance Immune response Immune system Immunomodulators In Vitro Inbred NOD Mice Inflammation Inflammatory Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Investigational Therapies Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Kidney Transplantation Life Liver Longevity Mediating Medical Methods Monitor Morbidity - disease rate Mus NOD/SCID mouse Nitrogen Outcome Outcome Study Oxidative Stress Oxygen Pancreas Pancreatic duct Pathway interactions Patient-Focused Outcomes Patients Peptide Hydrolases Pharmacologic Substance Phase Plasma Plasma Proteins Procedures Production Property Protease Inhibitor Proteins Publishing Reaction Recombinant Proteins Recombinants Reducing Agents Regulatory T-Lymphocyte Replacement Therapy Research Resistance Serine Proteinase Inhibitors Serpins Signal Pathway Structure Structure of beta Cell of islet T-Lymphocyte Technology Testing Therapeutic Total Pancreatectomy Toxicology Translating Transplantation Work alpha 1-Antitrypsin base burden of illness cell growth chronic pancreatitis clinically relevant design diabetes control early childhood effective therapy efficacious treatment efficacy study euglycemia experience global health immunoregulation improved in vivo insulin secretion islet mortality mouse model novel novel therapeutics oxidation post-transplant pre-clinical preimplantation preservation prevent response skills transplant model

项目摘要

PROJECT SUMMARY 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 diabetes accounts for 12% of the global health expenditure of which Type 1 diabetes mellitus (T1DM) constitutes 10-15% of the disease burden (IDF World Atlas 2015). T1DM is an autoimmune disease triggered by genetic and/or environmental factors in early childhood, resulting in T-cell mediated destruction of insulin producing pancreatic β-cells causing life-threatening hyperglycemia. Pancreatic β-cell transplantation is a promising experimental therapy that reverses diabetes in both animals and humans but is limited by the availability of donors and immune-mediated graft rejection and thus used primarily to control diabetes in patients who do not respond well to insulin replacement therapy or who develop severe complications. The discovery of new ways to induce tolerance without compromising a patient's immune system would be a major step forward in allowing wider adoption of β-cell transplantation as an effective therapy. One such protein displaying profound immunoregulatory effects is the human plasma protein alpha 1-antitrypsin (AAT, serpin A1) which is currently in clinical trials to improve pancreatic islet survival in patients undergoing renal transplantation, total pancreatectomy, or with difficult-to-control T1DM. Recently, the Kulkarni lab identified Serpin B1 (sB1) as a β-cell growth and survival factor. Serpin B1 is structurally and functionally related to AAT, and like AAT, is an effective anti-inflammatory protease inhibitor with immunoregulatory activities. However, sB1 also induces β-cell proliferation in vitro, promotes the neogenesis of insulin + cells in pancreatic ductal lining epithelia in vivo, induces immuno-tolerance by altering the Th17/Treg ratio in vivo and inhibits programmed cell death pathways not regulated by AAT. Independently, the Pemberton lab discovered that the protease inhibitory activity of sB1 can be rapidly inactivated by reactive oxygen and nitrogen (ROS/RNS) species and has formulated the protein with N-acetylcysteine to protect against this inactivation and mitigate the oxidative stress-induced inflammation, and pro-coagulant activities that islets are subject to during transplantation. We have demonstrated this formulation to prevent and treat new onset diabetes in the NOD mouse via mechanisms directly relevant to islet cell transplantation. Thus, we propose that sB1 will restore and maintain euglycemia in syngeneic (C57BL/6) and xenogeneic (NOD-SCID) mouse models of islet transplantation by protecting functional marginal β-cell masses against oxidative stress, IBMIR and inflammation while inducing their proliferation and enhancing immune tolerance by altering the Th17/Treg ratio. The proposed research in phase I will focus on producing highly purified active recombinant proteins and providing proof-of-principle in animal models of β-cell transplantation. The outcome of these studies will guide the design of future efficacy studies in animals and humans.

项目摘要全球糖尿病患者人数预计将从2015年的4.15亿增加到6.42亿在2040年治疗糖尿病的医疗保健费用占全球卫生支出的12%， 1型糖尿病（T1 DM）占疾病负担的10-15%（IDF World Atlas 2015）。T1 DM是一种由遗传和/或环境因素在儿童早期引发的自身免疫性疾病，导致T细胞介导破坏产生胰岛素的胰腺β细胞，导致危及生命的高血糖症。胰腺β细胞移植是一种很有前途的实验性治疗方法，但受供体可用性和免疫介导的移植排斥的限制，主要用于控制对胰岛素替代疗法反应不佳或出现严重并发症发现新的方法来诱导耐受性，而不损害患者的免疫系统将是允许更广泛地采用β细胞移植的重要一步，一种有效的疗法。显示出深刻免疫调节作用的一种这样的蛋白质是人血浆蛋白α 1-抗胰蛋白酶（AAT，丝氨酸蛋白酶抑制剂A1），目前正在临床试验中，以改善胰岛接受肾移植、全胰腺切除术或难以控制的T1 DM患者的生存率。最近，Kulkarni实验室将Serpin B1（sB 1）鉴定为β细胞生长和存活因子。Serpin B1是在结构和功能上与AAT相关，并且像AAT一样，是有效的抗炎蛋白酶抑制剂具有免疫调节活性。然而，sB 1也在体外诱导β细胞增殖，促进β细胞的增殖。体内胰腺导管衬里上皮中胰岛素+细胞的新生，通过改变体内Th 17/Treg比率，并抑制不受AAT调节的程序性细胞死亡途径。独立地， Pemberton实验室发现，sB 1的蛋白酶抑制活性可以通过反应性氧和氮（ROS/RNS）物种，并制定了蛋白质与N-乙酰半胱氨酸，以保护对抗这种失活并减轻氧化应激诱导的炎症和促凝血活性胰岛在移植过程中所受到的影响。我们已经证明了这种制剂可以预防和治疗通过与胰岛细胞移植直接相关的机制在NOD小鼠中新发糖尿病。因此，我们认为sB 1在同基因（C57 BL/6）和通过保护功能性边缘β细胞的胰岛移植的异种（NOD-SCID）小鼠模型在诱导其增殖的同时，通过改变Th 17/Treg比率增强免疫耐受性。第一阶段的拟议研究将集中于生产高纯度的活性重组蛋白并在β细胞移植的动物模型中提供原理验证。这些研究的结果将指导未来动物和人类疗效研究的设计。