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。