F31 Juan Medina

F31 胡安·梅迪纳

基本信息

批准号：
10157167
负责人：
Juan David Medina
金额：
$ 4.6万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
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：
2021-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10157167
关键词：
Address Adverse effects Agonist Allogenic Allografting American Antigens Apoptosis Autoimmune Diabetes Autoimmune Diseases Autoimmunity B-Lymphocytes Beta Cell Biocompatible Materials Blood Glucose CD95 Antigens Cell Death Cell Proliferation Cell Therapy Cell Transplantation Cells Chemicals Chronic Disease Clinical Clinical Trials Communication Coronary heart disease Data Diabetes Mellitus Diabetic mouse Diagnosis Disease Disease Progression Doctor of Philosophy Educational Curriculum Engineering Environment Equilibrium Eragrostis Exhibits Flow Cytometry Glucose tolerance test Graft Rejection Graft Survival Graft Tolerance Homologous Transplantation Hydrogels Immune Immune Tolerance Immunosuppression Immunotherapy Inbred BALB C Mice Inbred NOD Mice Individual Insulin Insulin-Dependent Diabetes Mellitus Interleukin-2 Islets of Langerhans Transplantation Kidney Diseases Kinetics Leadership Life Light Lymphoid Lymphoid Cell Maleimides Mediating Mentors Modeling Monitor Myelogenous Neuropathy Oral Outcome Pancreas Patients Population Prediabetes syndrome Proteins Recombinants Regimen Regulatory T-Lymphocyte Research Signal Transduction Sirolimus Site Streptavidin Structure of beta Cell of islet T-Lymphocyte Testing Training Transplantation Up-Regulation Work arm autoimmune pathogenesis autoreactivity base blood glucose regulation controlled release cost diabetic effector T cell efficacy evaluation graft function immunoregulation improved in vivo imaging innovation insulin dependent diabetes mellitus onset insulitis islet islet allograft meetings mouse model novel particle prevent restoration skills success trait type I diabetic

项目摘要

Project Summary Type 1 diabetes (T1D), an autoimmune disorder prevalent in 1.6 million Americans, is growing rapidly with 64,000 yearly diagnoses and costing the U.S. $16 billion annually. Pancreatic islet transplantation has shown promise in treating T1D, however, immune rejection and continuous use of immunosuppression to control rejection limit clinical islet transplantation. Standard immunosuppression is ineffective in achieving long-term graft survival and has significant adverse effects on graft recipients as ~50% of recipients maintain insulin independence at five years. Therefore, there is a significant need to prevent graft rejection without an immunosuppressive regimen. Uncontrolled expansion of islet-reactive T effector (Teff) cells in pre-diabetics reaches a point where it cannot be contained by protective T regulatory (Treg) cells. This further complicates transplantation of allogeneic islets due to rejection by both alloreactive and autoreactive Teff cells. To tilt the balance in favor of Treg cells, approaches have targeted Teff or Treg cells individually for modulation with limited success. The objective of this project is to target Treg and Teff cells simultaneously by engineering a novel biomaterial strategy to achieve localized immunotolerance to islet allografts. Since Teffs activated by antigens express Fas receptor, becoming sensitive to FasL-mediated apoptosis, a chimeric form of the Fas agonist, FasL, and a streptavidin core has been engineered (SA-FasL), to be presented on biotinylated biomaterials and induce Teff apoptosis. Since IL-2R signaling preferentially sensitizes Teff cells to Fas-induced cell death while promoting Treg expansion, a recombinant IL-2R agonist has been engineered, IL-2D, to be presented alongside SA-FasL. The central hypothesis is that controlled delivery of SA-FasL/IL-2D via engineered biomaterials will increase the number of antigen-specific Tregs and decrease the number of antigen-specific Teffs, creating an immune-tolerant microenvironment at the graft site that prolongs islet graft survival in the absence of systemic immunosuppression. Preliminary data support this hypothesis and provide strong scientific premise and feasibility for this application, which will be accomplished across two specific aims: 1) Engineer a synthetic hydrogel platform that delivers SA-FasL and IL-2D to induce immune tolerance to transplanted islets. 2) Evaluate the efficacy of the IL-2D/SA-FasL hydrogel to achieve sustained graft survival in a spontaneously diabetic NOD mouse model. Expected outcomes include local immune tolerance in the absence of immunosuppression by the controlled release of IL-2D/SA-FasL and a greater understanding of the mechanisms responsible for the induction immune privilege. If accepted, the applicant will also undergo training aimed at developing 1) technical and analytical research skills, 2) oral and written communication skills, 3) strong leadership traits, and 4) entrepreneurial expertise. Direct mentoring from Dr. García, the Georgia Tech BME Ph.D. curriculum, and participation in scientific meetings will facilitate this training.

项目概要 1 型糖尿病 (T1D) 是一种在 160 万美国人中流行的自身免疫性疾病，随着每年有 64,000 例诊断，胰岛移植费用高达 160 亿美元。治疗 T1D 的希望，然而，免疫排斥和持续使用免疫抑制来控制排斥反应限制了临床胰岛移植，标准免疫抑制无法实现长期效果。移植物存活并对移植物受者产生显着的不利影响，因为约 50% 的受者维持胰岛素因此，非常需要在没有移植物的情况下预防移植排斥。糖尿病前期患者的胰岛反应性 T 效应细胞 (Teff) 不受控制地扩增。达到了保护性 T 调节 (Treg) 细胞无法控制的程度。由于同种异体反应性和自身反应性 Teff 细胞的排斥而进行同种异体胰岛移植。有利于 Treg 细胞的平衡，方法已分别针对 Teff 或 Treg 细胞进行调节该项目的目标是通过工程化同时靶向 Treg 和 Teff 细胞。自从Teffs激活以来，新的生物材料策略实现了对胰岛同种异体移植物的局部免疫耐受。抗原表达 Fas 受体，对 FasL 介导的细胞凋亡（Fas 的嵌合形式）变得敏感激动剂 FasL 和链霉亲和素核心已被设计 (SA-FasL)，将呈现在生物素化的由于 IL-2R 信号优先使 Teff 细胞对 Fas 诱导敏感。细胞死亡同时促进 Treg 扩增，重组 IL-2R 激动剂 IL-2D 已被设计为与 SA-FasL 一起提出的中心假设是 SA-FasL/IL-2D 的控制传递通过工程生物材料将增加抗原特异性Treg的数量并减少抗原特异性 Teffs，在移植部位创造免疫耐受的微环境，延长胰岛寿命在没有全身免疫抑制的情况下移植物存活。初步数据支持这一假设。为本次应用提供了强有力的科学前提和可行性，该应用将分两期完成具体目标：1) 设计一个合成水凝胶平台，提供 SA-FasL 和 IL-2D 以诱导免疫 2) 评估 IL-2D/SA-FasL 水凝胶实现持续性的功效。预期结果包括局部免疫在没有免疫抑制的情况下通过控制 IL-2D/SA-FasL 的释放和更大的耐受性了解负责诱导免疫特权的机制如果接受，申请人将。还接受旨在发展 1) 技术和分析研究技能，2) 口头和书面能力的培训沟通技巧，3) 强大的领导才能，以及 4) 博士的直接指导。 García、佐治亚理工学院 BME 博士课程以及参加科学会议将促进这一培训。