Preclinical Studies of Novel Anti-Diabetic Lipids

由于肥胖、胰岛素抵抗和2型糖尿病日益流行，我们需要针对这些严重疾病的更有效和可持续的预防和治疗策略。我们对胰岛素抵抗和2型糖尿病的分子机制的认识存在重大差距，这限制了我们开发完全有效和安全的疗法来治疗这些代谢疾病的能力。在这个应用中，我们努力开发一类新的抗糖尿病药物，其基础是我们最近发现的一种结构新颖的生物活性脂类，称为羟基脂肪酸脂肪酸酯（FAHFAs）。对羟基硬脂酸棕榈酸酯（PAHSAs）家族的表征表明，这些脂质具有显著的改善葡萄糖代谢和减少炎症的活性。PAHSAs刺激肥胖小鼠胰岛素分泌和GLP1分泌，提高全身胰岛素敏感性（即胰岛素增敏剂），减少脂肪组织中促炎细胞因子的分泌。作为天然化合物，PAHSAs不是为特定目标而设计的。相反，这些脂质通过至少两个G蛋白偶联受体（gpcr）利用多种途径。这种有益活性和受体靶点的强大组合使PAHSAs成为治疗糖尿病的一种令人兴奋的新型化合物。在Aim 1中，我们将设计、合成和测试PAHSA和PAHSA类似物，以提高溶解度、生物活性和代谢稳定性。当我们合成PAHSA类似物时，这个过程将是迭代的，我们将在目标1和目标2的生物分析和代谢稳定性研究中对它们进行测试，并利用这些信息设计具有改进性能的下一代类似物。在目标2中，我们将研究PAHSA和PAHSA类似物的药代动力学、疗效和毒性，以确定哪些化合物具有理想的稳定性、口服利用度、安全性和活性。这些实验的信息也将有助于在Aim 1中设计新的PAHSA类似物。然后在Aim 3中，我们将通过敲除小鼠和这些小鼠组织的生物学测定来确定GPR40和GPR120在体内介导PAHSA生物效应中的作用。药物进入临床需要明确的作用机制，而PAHSAs靶向两种备受关注的抗糖尿病GPCR药物靶点的发现将增加开发基于pahsa的药物的兴趣。我们还将进行广泛的靶标筛选，因为PAHSAs可能有额外的受体或途径。结合Aim 3中获得的数据，将全面了解GPR40、GPR120和其他PAHSA靶点对体内PAHSA生物学的贡献。该应用程序将提供结构、药代动力学、毒理学和机理数据，以开发PAHSA或PAHSA类似物作为新型抗糖尿病药物。

Because of the growing epidemic of obesity, insulin resistance, and Type 2 diabetes, we need more effective and sustainable prevention and treatment strategies for these serious disorders. Significant gaps exist in our knowledge of the molecular mechanisms underlying insulin resistance and Type 2 diabetes, which limit our ability to develop fully effective and safe therapies to treat these metabolic diseases. In this application, we strive to develop a new class of antidiabetic therapeutics based on a structurally novel class of bioactive lipids we recently discovered called Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs). Characterization of one family of FAHFAs, Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), revealed that these lipids possess a remarkable range of activities that improve glucose metabolism and reduce inflammation. PAHSAs stimulate insulin secretion and GLP1 secretion, improve systemic insulin sensitivity (i.e. they are insulin sensitizers), and reduce proinflammatory cytokine secretion in adipose tissue of obese mice. As natural compounds, PAHSAs were not designed for a particular target. Instead, these lipids utilize multiple pathways through at least two G protein coupled receptors (GPCRs). This powerful combination of beneficial activities and receptor targets uniquely positions PAHSAs as an exciting new class of compounds for the treatment of diabetes. In Aim 1, we will design, synthesize, and test PAHSAs and PAHSA analogs to enhance solubility, biological activity, and metabolic stability. This process will be iterative as we synthesize PAHSA analogs we will test them in biologic assays and metabolic stability studies in Aims 1 and 2 and use this information to design the next generation of analogs with improved properties. In Aim 2, we will investigate pharmacokinetics, efficacy, and toxicity of PAHSAs and PAHSA analogs to determine which compounds have the ideal stability, oral availability, safety, and activity. The information from these experiments will also assist in the design of new PAHSA analogs in Aim 1. Then in Aim 3, we will determine the roles of GPR40 and GPR120 in mediating PAHSA biological effects in vivo using knockout mice and biologic assays in tissues from these mice. A clear mechanism of action is required for drugs moving into the clinic, and the finding that PAHSAs target two intensely pursued anti-diabetic GPCR drug targets will amplify interest in developing PAHSA-based drugs. We will also perform broad target screening since PAHSAs might have additional receptors or pathways. The combination of the data obtained in Aim 3 will provide a comprehensive understanding of the contribution of GPR40, GPR120, and other PAHSA targets to PAHSA biology in vivo. This application will provide the structural, pharmacokinetic, toxicology, and mechanistic data needed to develop PAHSAs or PAHSA analogs into novel anti-diabetes therapeutics.