Role of TLR9 in beta cell function and diabetes

描述(申请人提供)：在这项申请中，我们建议研究TRL9在免疫和胰岛β细胞功能和糖尿病中的作用。我们的初步数据表明，TLR9缺陷小鼠的胰岛β细胞功能增强，并对1型糖尿病和高脂饮食诱导的肥胖具有抵抗力。我们建议对这一新发现进行调查，并相信一旦我们了解了TLR9如何调节β细胞功能的基本机制，我们将能够向公众提供更好的知识，并有望设计出更好的预防和/或治疗策略。我们提出了3个具体目标来实现这一目标：1)：我们假设TLR9拮抗剂将促进β细胞的发育和功能，从而对T1D的发展具有预防和/或治疗作用。为了验证这一假设，我们将用TLR9拮抗剂治疗小鼠，并研究其对糖尿病发展的影响。2)：我们假设TLR9在肥胖和T2D的发展中起作用。我们将通过使用高脂诱导肥胖(HFIO)模型研究免疫细胞、脂肪细胞和胰岛β细胞的功能来检验这一假设。我们还假设TLR9拮抗剂将改善这些细胞的功能和β细胞的发育，并将对肥胖和T2D的发展具有预防和/或治疗作用。我们将通过用TLR9拮抗剂治疗野生型小鼠来验证这一假设，并研究其对肥胖和T2D发育的影响。3)：我们假设TLR9在免疫和胰岛β细胞中的恢复将逆转TLR9-/-小鼠的表型。为了验证我们的假设，我们将在细胞特异性启动子下将TLR9作为转基因引入我们的TLR9缺陷小鼠中。我们将研究免疫和胰岛β细胞的功能以及对这些小鼠糖尿病发展的影响。 公共卫生相关性：越来越多的证据表明，在包括1型和2型糖尿病在内的许多健康问题中，先天免疫受体的触发与炎症之间存在联系。先天免疫受体可以检测环境刺激。我们的初步数据表明，TLR9缺陷小鼠的胰岛β细胞功能增强，并对1型糖尿病和高脂肪诱导的肥胖/胰岛素抵抗具有抵抗力。我们建议对这一新发现进行研究，并相信一旦我们了解了TLR9如何调节免疫细胞和胰岛β细胞功能的基本机制，我们就能够向公众提供更好的知识，并有望设计出更好的预防和/或治疗策略。

DESCRIPTION (provided by applicant): In this application, we propose to study the role of TRL9 in immune and islet beta cell function and diabetes. Our preliminary data suggest that TLR9 deficient mice have enhanced islet beta cell function and are resistant to type 1 diabetes development and high fat diet induced obesity. We propose to investigate this novel finding and believe that once we understand the basic mechanisms of how TLR9 regulates beta cell function, we will be able to provide better knowledge to the public and hopefully to design better preventive and/or therapeutic strategies. We propose 3 specific aims to achieve this goal: 1): We hypothesize that TLR9 antagonists will improve beta cell development and function, and therefore, will have preventive and/or therapeutic effects on T1D development. To test this hypothesis, we will treat mice with a TLR9 antagonist and study the effect on diabetes development. 2): We hypothesize that TLR9 plays a role in obesity and T2D development. We will test this hypothesis by investigating the function of immune cells, adipocytes and islet beta cells using a high fat induced obesity (HFIO) model. We also hypothesize that TLR9 antagonists will improve the function of these cells and beta cell development and will have preventive and/or therapeutic effects on obesity and T2D development. We will test this hypothesis by treating wild type mice with a TLR9 antagonist and study the effect on obesity and T2D development. 3): We hypothesize that restoration of TLR9 in immune and islet beta cells will reverse the phenotype seen in TLR9-/- mice. To test our hypothesis, we will introduce TLR9 as a transgene in our TLR9 deficient mice under cell specific promoters. We will study the functions of immune and islet beta cells and the effect on diabetes development in these mice. PUBLIC HEALTH RELEVANCE: Increasing evidence suggests a link between triggering of innate immune receptors, which detect environmental stimuli, and inflammation in many health problems including type 1 and type 2 diabetes. Our preliminary data suggest that TLR9 deficient mice have enhanced islet beta cell function and are resistant to type 1 diabetes development and high fat induced obesity/insulin resistance. We propose to investigate this novel finding and believe that once we understand the basic mechanisms of how TLR9 regulates immune cell and islet beta cell function, we will be able to provide better knowledge to the public and hopefully t design better preventive and/or therapeutic strategies.