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羟氨酸抑制剂（MMPIS）来阻止胰岛素依赖性糖尿病（I型糖尿病； IDDM）的进展。透明质酸结合CD44是粘附和信号受体。细胞表面相关的CD44与膜型1基质金属蛋白酶（MT1-MMP）之间的相互关系对于有效的粘附和T杀手细胞的跨内皮迁移至兰格汉胰岛都是必不可少的。穿透到胰岛后，细胞毒性T细胞会导致胰岛素产生P细胞的破坏。我们已经证明，MT1-MMP蛋白水解是T细胞CD44动态调节的关键因素，并且随后糖尿病生成的IS-CD8* t杀伤细胞的胰岛特异性归位。抑制剂诱导的MT1-MMP和CD44之间的相互关系变化干扰了T杀伤细胞向胰腺的粘附，移民和归巢，并导致NOD小鼠中糖尿病的发作显着延迟。这种啮齿动物模型发展出一种非常类似于人IDDM的疾病。我们将扩展我们的发现，并开发一种具有成本效益且可靠的体内策略，以使用现有和可用的无毒羟氨基MMPI来抑制T细胞CD44的MT1-MMP蛋白水解。这些MMPI已在癌症患者中进行了测试，事实证明是无毒的，并且很容易从大型制药公司那里获得。我们假设通过低剂量的MMPIS抑制MT1-MMP蛋白水解对T细胞CD44的抑制是一种新型的，非常有前途的方法，并改善了IDDM的治疗方法。我们的方法基于我们对MMP的广泛和深入了解，尤其是我们对MT1-MP/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”，我们将测试可用的Hydroxamates GM6001和AG3340。作为对照，我们将使用对MMP-2和MMP-9有效的非羟氨酸SB3CT硫醇抑制剂，但对MT1-MMP无效。我们的具体目的是：（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MT1-MMP的小分子拮抗剂的药理价值（Hydroxamates GM6001和AG33340和AG3340和AG3340和AG3340，以及AG3340，以及AG3340，以及AG3340，以及AG3340，以及糖尿病的产物转移和（3）以验证MT1-MMP的小分子拮抗剂的药理学值（Hydroxamates GM6001和AG3340，以及硫醇化合物SB3CT）在糖尿病前和新鲜疾病的疾病中。我们坚信的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。