DIACEST Islet Cell Capsules for Immunoprotection, MR Detection, and pH Sensing

用于免疫保护、MR 检测和 pH 传感的 DIACEST 胰岛细胞胶囊

基本信息

批准号：
8146032
负责人：
MICHAEL T MCMAHON
金额：
$ 33.8万
依托单位：
HUGO W. MOSER RES INST KENNEDY KRIEGER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-22 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8146032
关键词：
Acute Liver Failure Alginates Amino Acids Antibodies Apoptosis Arginine Attention Biocompatible Cell Line Cell Survival Cell Therapy Cell physiology Cells Chemicals Clinic Clinical Color Contrast Media Crosslinker Detection Diabetic mouse Discrimination Disease Encapsulated Environment Firefly Luciferases Goals Hemophilia A Human Image Imagery In Vitro Individual Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Label Libraries Life Lipids Liposomes Magnetic Resonance Magnetic Resonance Imaging Malignant Neoplasms Measures Membrane Mesenchymal Mesenchymal Stem Cells Metals Methods Microencapsulations Monitor Mus Parkinson Disease Patients Peptides Physiological Population Production Reporting Signal Transduction Source Staging Stem cells Streptozocin Techniques Testing Therapeutic immunosuppression Time Toxic effect Treatment Protocols Validation base capsule cell capsule design functional status glycemic control in vivo insulin secretion insulinoma islet mouse model pre-clinical preclinical study prevent public health relevance remote sensing small molecule libraries success

项目摘要

DESCRIPTION (provided by applicant): Good glycemic control is critical in reducing the end-stage complications of Type I Diabetes Mellitus (TIDM) and, for this reason, islet transplantation (ITx) has received considerable attention in recent years, with one of the complications in the treatment involves finding an effective means to prevent rejection. Immuno-isolation of islets provides a means to reduce or avoid immunosuppressive therapy altogether. In the most commonly used method of immuno-isolation, microencapsulation, individual islets are surrounded with thin alginate membranes that are permeable to insulin and metabolites, but are impermeable to native antibodies. However, the viability and in particular the insulin secretion of these islets are critical for the success of the therapy, and would be important to monitor for refinement of the treatment protocol. This proposal is focused on the production of micron sized CEST MR detectable alginate capsules containing both islet and mesenchymal stem cells which are appropriate for the treatment of T1DM. These capsules will have CEST MR contrast agents built into the capsule to allow: 1) detection, 2) discrimination between encapsulated islet and mesynchymal stem cells and 3) remote sensing of the pH of the environment. The source of the CEST contrast will be 6-24 amino acid long peptides and CEST liposomes embedded within the alginate. We will perform pre-clinical studies using a nude based mouse model of diabetes to allow monitoring of the status of encapsulated islets/ mesenchymal cells through firefly luciferase expression. PUBLIC HEALTH RELEVANCE: Islet transplantation (ITx) has received considerable attention in recent years for treatment of Type 1 Diabetes Melitus (T1DM). This proposal is focused on the production of immunoprotective islet cell capsules which are appropriate for treatment and allow MR monitoring of the pH these islets using biodegradable CEST contrast agents.

描述（由申请人提供）：良好的血糖控制对于减少 I 型糖尿病 (TIDM) 的终末期并发症至关重要，因此，胰岛移植 (ITx) 近年来受到了相当大的关注，其中之一治疗中的并发症包括寻找有效的方法来预防排斥反应。胰岛的免疫隔离提供了一种减少或完全避免免疫抑制治疗的方法。在最常用的免疫分离方法中，微囊化，单个胰岛被薄藻酸盐膜包围，该膜可渗透胰岛素和代谢物，但不可渗透天然抗体。然而，这些胰岛的活力，特别是胰岛素分泌对于治疗的成功至关重要，并且对于监测治疗方案的完善也很重要。该提案的重点是生产微米级 CEST MR 可检测藻酸盐胶囊，其中含有胰岛干细胞和间充质干细胞，适合治疗 T1DM。这些胶囊将内置 CEST MR 造影剂，以实现：1) 检测，2) 区分封装的胰岛和间充质干细胞，以及 3) 遥感环境 pH 值。 CEST 对比剂的来源是 6-24 个氨基酸的长肽和嵌入藻酸盐内的 CEST 脂质体。我们将使用糖尿病裸鼠模型进行临床前研究，以便通过萤火虫荧光素酶表达监测封装的胰岛/间充质细胞的状态。公众健康相关性：近年来，胰岛移植 (ITx) 用于治疗 1 型糖尿病 (T1DM) 受到了广泛关注。该提案的重点是生产免疫保护性胰岛细胞胶囊，该胶囊适用于治疗，并允许使用可生物降解的 CEST 造影剂对这些胰岛的 pH 值进行 MR 监测。