Hydroxamate-based therapy to target T cell homing in IDDM

描述（由申请人提供）：我们的目标是通过使用小分子羟酸盐抑制剂（MMPIs）阻断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是一种粘附和信号受体。细胞表面相关CD44和膜型1基质金属蛋白酶（MT1-MMP）之间的相互关系对于T杀伤细胞有效粘附和跨内皮迁移到朗格汉斯胰岛至关重要。渗入胰岛后，细胞毒性T细胞破坏产生胰岛素的p细胞。我们已经证明MT1-MMP蛋白水解是T细胞CD44和随后的胰岛特异性归巢的糖尿病性is - cd8 * T杀伤细胞的动态调节的关键因素。抑制剂诱导的MT1-MMP和CD44之间相互关系的改变干扰了T杀伤细胞到胰腺的粘附、迁移和归巢，并导致NOD小鼠糖尿病发病的显著延迟。这种啮齿动物模型发展出一种与人类IDDM非常相似的疾病。我们将扩展我们的研究结果，并开发一种经济有效和可靠的体内策略，通过使用现有的和可用的无毒羟酸MMPIs来抑制T细胞CD44的MT1-MMP蛋白水解。这些mmpi已经在癌症患者身上进行了测试，证明是无毒的，并且很容易从大型制药公司获得。我们假设，低剂量MMPIs抑制T细胞CD44的MT1-MMP蛋白水解是一种新的、非常有前途的方法，可以改善IDDM的治疗。我们的方法完全基于我们对MMPs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”，我们将测试可用的羟酸盐GM6001和AG3340。作为对照，我们将使用非羟化SB3CT硫醇抑制剂，它对MMP-2和MMP-9有效，但对MT1-MMP无效。我们的具体目标是：(1)确定MT1-MMP蛋白水解T细胞CD44对IS-CD8* T杀伤细胞粘附和迁移的生理影响；(2)验证MT1-MMP小分子拮抗剂（羟酸酯GM6001和AG3340，以及巯基化合物SB3CT）在糖尿病过继性转移啮齿动物模型中的药理价值；(3)验证MT1-MMP小分子拮抗剂（羟酸酯GM6001和AG3340）的药理价值；和硫醇化合物SB3CT)在糖尿病前期和新发病NOD小鼠。我们坚信，的结果

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.