Role of TLR9 in beta cell function and diabetes

描述（由申请人提供）：在本次申请中，我们拟研究TRL9在免疫和胰岛β细胞功能以及糖尿病中的作用。我们的初步数据表明，TLR9缺陷小鼠具有增强的胰岛β细胞功能，并且对1型糖尿病的发展和高脂肪饮食诱导的肥胖具有抗性。我们建议研究这一新发现，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，我们将能够为公众提供更好的知识，并有望设计更好的预防和/或治疗策略。我们提出了实现这一目标的3个具体目标：1)：我们假设TLR9拮抗剂将改善β细胞的发育和功能，因此，将对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发展中起作用。我们将通过使用高脂性肥胖（HFIO）模型研究免疫细胞、脂肪细胞和胰岛β细胞的功能来验证这一假设。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，并对肥胖和T2D的发展具有预防和/或治疗作用。我们将通过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发展的影响。我们假设免疫细胞和胰岛β细胞中TLR9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TLR9缺陷小鼠。我们将在这些小鼠中研究免疫细胞和胰岛β细胞的功能及其对糖尿病发展的影响。

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.