Hydroxamate-based therapy to target T cell homing in IDDM

IDDM 中基于异羟肟酸盐的靶向 T 细胞归巢疗法

基本信息

批准号：
7295821
负责人：
Alex Y Strongin
金额：
$ 27.82万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-20 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7295821
关键词：
Adhesions Adoptive Transfer Ag3340 Antineoplastic Agents Binding Birth CD44 Antigens CD44 gene Cancer Patient Cell surface Cells Cytotoxic T-Lymphocytes Depth Development Diabetes Mellitus Disease Endothelial Cells Event Female Fostering GM 6001 Gelatinase A Gelatinase B Goals Homing Human Hyaluronan Inbred NOD Mice Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Knowledge Lead Malignant Neoplasms Matrix Metalloproteinases Mediating Membrane Metalloproteases Modeling Mus Non obese Pancreas Patients Penetration Pharmaceutical Preparations Pharmacologic Substance Physiological Production Proteolysis Quality of life Receptor Signaling Rodent Model Role Severity of illness Signal Transduction Sulfhydryl Compounds T cell regulation T-Lymphocyte Testing base clinical application cost diabetic dosage human MMP14 protein hydroxamate improved in vivo inhibitor/antagonist islet killer T cell migration novel programs small molecule

项目摘要

DESCRIPTION (provided by applicant): Our goal is to block the progression of insulin-dependent diabetes mellitus (type I diabetes; IDDM) by using small molecule hydroxamate inhibitors (MMPIs). Hyaluronan-binding CD44 is an adhesion and signaling receptor. The reciprocal relationship between cell surface-associated CD44 and membrane-type 1 matrix metalloproteinase (MT1-MMP) is essential for both efficient adhesion and for transendothelial migration of T killer cells into the islets of Langerhans. After penetration into the islets, cytotoxic T cells cause the destruction of insulin-producing p cells. We have demonstrated that MT1-MMP proteolysis is a key factor in the dynamic regulation of T cell CD44 and the subsequent islet-specific homing of diabetogenic IS-CD8* T killer cells. Inhibitor-induced changes in the reciprocal relationship between MT1-MMP and CD44 interfere with adhesion, transmigration and homing of T killer cells to the pancreas, and cause a significant delay in the onset of diabetes in NOD mice. This rodent model develops a disease closely resembling human IDDM. We will extend our findings and develop a cost-efficient and reliable in vivo strategy to inhibit MT1-MMP proteolysis of T cell CD44 by using existing and available, non-toxic hydroxamate MMPIs. These MMPIs have been tested in cancer patients, proved to be non-toxic and are readily available from major pharmaceutical companies. We hypothesize that the inhibition of MT1-MMP proteolysis of T cell CD44 by low dosages of MMPIs is a novel, highly promising approach and improved therapy of IDDM. Our approach is soundly based on our extensive and in-depth knowledge of MMPs and, especially, on our understanding of the functional role of the MT1-MMP/CD44 interactions in cancer and diabetes. As a "proof-of-principal" we will test the available hydroxamates GM6001 and AG3340. As a control, we will use the non-hydroxamate SB3CT thiol inhibitor that is potent against MMP-2 and MMP-9 but it is not effective against MT1-MMP. Our specific aims are: (1) To determine the physiological impact of the MT1-MMP proteolysis of T cell CD44 on the adhesion and migration of IS-CD8* T killer cells, (2) To validate the pharmacological value of the small molecule antagonists of MT1-MMP (the hydroxamates GM6001 and AG3340, and the thiol compound SB3CT) in a rodent model of adoptive transfer of diabetes, and (3) To validate the pharmacological value of the small molecule antagonists of MT1-MMP (the hydroxamates GM6001 and AG3340, and the thiol compound SB3CT) in pre-diabetic and freshly diseased NOD mice. We strongly believe that the results of our experimental program will lead to the development of new and effective anti-diabetic therapies for IDDM patients.

描述（由申请人提供）：我们的目标是通过使用小分子异羟肟酸抑制剂（MMPI）来阻止胰岛素依赖型糖尿病（I 型糖尿病；IDDM）的进展。透明质酸结合 CD44 是一种粘附和信号传导受体。细胞表面相关 CD44 和膜 1 型基质金属蛋白酶 (MT1-MMP) 之间的相互关系对于 T 杀伤细胞的有效粘附和跨内皮迁移至朗格汉斯岛至关重要。细胞毒性 T 细胞渗透到胰岛后，会破坏产生胰岛素的 p 细胞。我们已经证明，MT1-MMP 蛋白水解是 T 细胞 CD44 动态调节以及随后致糖尿病 IS-CD8* T 杀伤细胞的胰岛特异性归巢的关键因素。抑制剂诱导的 MT1-MMP 和 CD44 之间相互关系的变化会干扰 T 杀伤细胞向胰腺的粘附、迁移和归巢，并导致 NOD 小鼠糖尿病的发病显着延迟。这种啮齿动物模型会产生一种与人类 IDDM 非常相似的疾病。我们将扩展我们的发现并开发一种经济有效且可靠的体内策略，通过使用现有的和可用的无毒异羟肟酸 MMPI 来抑制 T 细胞 CD44 的 MT1-MMP 蛋白水解。这些 MMPI 已经在癌症患者中进行了测试，被证明是无毒的，并且可以从主要制药公司轻松获得。我们假设低剂量的 MMPI 抑制 T 细胞 CD44 的 MT1-MMP 蛋白水解是一种新颖的、非常有前途的方法，也是 IDDM 的改进疗法。我们的方法完全基于我们对 MMP 的广泛而深入的了解，特别是我们对 MT1-MMP/CD44 相互作用在癌症和糖尿病中的功能作用的理解。作为“原理证明”，我们将测试现有的异羟肟酸盐 GM6001 和 AG3340。作为对照，我们将使用非异羟肟酸酯 SB3CT 硫醇抑制剂，该抑制剂对 MMP-2 和 MMP-9 有效，但对 MT1-MMP 无效。我们的具体目标是：(1) 确定 T 细胞 CD44 的 MT1-MMP 蛋白水解对 IS-CD8* T 杀伤细胞的粘附和迁移的生理影响，(2) 验证小分子拮抗剂的药理价值MT1-MMP（异羟肟酸盐 GM6001 和 AG3340，以及硫醇化合物 SB3CT）在糖尿病过继转移的啮齿动物模型中的作用，以及（3）验证 MT1-MMP 小分子拮抗剂（异羟肟酸盐 GM6001 和 AG3340，以及硫醇化合物 SB3CT）在糖尿病前期和新患病 NOD 小鼠中的药理学价值。我们坚信，结果我们的实验计划将为 IDDM 患者开发新的有效的抗糖尿病疗法。