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IL2-based Immunotherapy for Type 2 Diabetes

IL2-based Immunotherapy for Type 2 Diabetes
基于 IL2 的 2 型糖尿病免疫疗法
批准号:
9135661
负责人:
RIDONG CHEN
金额:
$29.92万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-05-01 至 2017-08-31

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项目成果

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中文摘要
翻译
 描述(由申请人提供):主要研究者/项目负责人(最后,第一,中间:陈日东摘要2型糖尿病(T2 D)是心血管疾病、肾衰竭、失明、截肢和住院的主要原因。高达80%的T2 D患者超重或肥胖,这会诱导脂肪组织的慢性低度炎症,并促进胰岛素抵抗和T2 D。此外,体重增加是较老的抗糖尿病药物的常见副作用。目前的疗法不能治愈,需要每天给药。因此,迫切需要改善葡萄糖控制同时减轻体重的新疗法。CD 4 + CD 25 + Foxp 3+调节性T细胞(Treg)调节炎症和胰岛素抵抗。非常有趣的是,具有独特表型的Treg细胞在正常动物的内脏脂肪组织(VAT)中高度富集,但它们的数量在肥胖动物的胰岛素抵抗模型中显著且特异性地减少。重要的是,在肥胖的人网膜中也发现Treg数量减少。白细胞介素-2(IL-2)是通过与其高亲和力受体直接结合而使Treg产生、存活和发挥功能的关键细胞因子。 因此,用低剂量IL 2恢复VAT Treg细胞可以提供用于减轻肥胖相关的低度炎症和逆转胰岛素抵抗和T2 D的新策略。我们已经设计了一种基于IL 2的疗法,该疗法将能够选择性刺激TGFAP。在拟定的I期SBIR研究中,我们将确定每周一次治疗4周是否会改善肥胖db/db小鼠和饮食诱导肥胖小鼠的T2 D模型中的胰岛素敏感性和血糖控制,同时减少体重过度增加。该项目的长期目标是开发一种新的T2 D治疗(每周或每两周一次),单独或与当前治疗联合使用,以改善葡萄糖稳态并减轻糖尿病相关并发症,同时减少体重过度增加。
英文摘要
 DESCRIPTION (provided by applicant): Principal Investigator/Program Director (Last, First, Middle: Chen, Ridong Abstract Type-2 diabetes (T2D) is a leading cause of cardiovascular disease, renal failure, blindness, amputations and hospitalization. Up to 80% of T2D patients are overweight or obese, which induces chronic, low-grade inflammation of adipose tissue and promotes insulin resistance and T2D. Moreover, weight gain is the common side-effect of older anti-diabetic drugs. Current therapies are not a cure and require daily administration. Hence, novel therapy that improves glucose control while simultaneously reducing body weight is urgently needed. CD4+CD25+Foxp3+ regulatory T cells (Treg) modulate inflammation and insulin resistance. Very interestingly, Treg cells with a unique phenotype are highly enriched in the visceral adipose tissue (VAT) of normal animals, but their numbers are strikingly and specifically reduced in insulin-resistant models of obese animals. Importantly, decreased numbers of Treg are also found in obese human omental. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of Treg by direct binding to its high affinity receptor. Hence, restoration of VAT Treg cells with low-dose IL2 may offer a novel strategy for mitigating obesity related low-grade inflammation and reversing insulin resistance and T2D. We have designed an IL2-based therapy that will enable selective stimulation of Tregs. In the proposed Phase I SBIR study, we will determine whether weekly treatment for 4 weeks leads to improvement of insulin sensitivity and glucose control, while reducing excessive body weight gain in the T2D models of obese db/db mice and diet-induced obese mice. The long-term goal of this project is to develop a novel treatment (weekly or bi-weekly) for T2D, alone or in combination with current therapies, to improve glucose homeostasis and attenuate diabetes-associated complications while simultaneously reducing excessive body weight gain.
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海外基金