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

• 批准号: 7192269
• 负责人: Alex Y Strongin
• 金额: $ 23.88万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 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/7192269
• 关键词: CD44 molecule; NOD mouse; T lymphocyte; cell adhesion; cell migration; cost effectiveness; cytotoxic T lymphocyte; diabetes mellitus therapy; disease /disorder model; flow cytometry; hydroxamate; inhibitor /antagonist; insulin dependent diabetes mellitus; laboratory mouse; metalloendopeptidases; nonhuman therapy evaluation; pancreatic islets; pathologic process; proteolysis; small molecule; therapy design /development; thiols; western blottings

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。