Preclinical Studies of Novel Anti-Diabetic Lipids

新型抗糖尿病脂质的临床前研究

基本信息

  • 批准号:
    9515379
  • 负责人:
  • 金额:
    $ 90.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-04 至 2019-08-31
  • 项目状态:
    已结题

项目摘要

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.
由于肥胖、胰岛素抵抗和2型糖尿病的流行日益严重,我们需要更有效和可持续的预防和治疗策略来应对这些严重疾病。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治疗这些代谢疾病的疗法的能力。在本申请中,我们致力于开发一类新的抗糖尿病治疗剂,其基于我们最近发现的一类结构新颖的生物活性脂质,称为羟基脂肪酸的脂肪酸酯(FAHFA)。FAHFA的一个家族,羟基硬脂酸的棕榈酸酯(PAHSAs)的表征揭示了这些脂质具有改善葡萄糖代谢和减少炎症的显著范围的活性。PAHSA刺激胰岛素分泌和GLP 1分泌,改善全身胰岛素敏感性(即它们是胰岛素增敏剂),并减少肥胖小鼠脂肪组织中的促炎细胞因子分泌。作为天然化合物,PAHSAs不是针对特定目标而设计的。相反,这些脂质通过至少两个G蛋白偶联受体(GPCR)利用多个途径。这种有益活性和受体靶点的强大组合使PAHSAs成为治疗糖尿病的令人兴奋的新化合物。在目标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2中的生物测定和代谢稳定性研究中对其进行测试,并使用这些信息来设计具有改进性质的下一代类似物。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。来自这些实验的信息也将有助于目的1中新的PAHSA类似物的设计。然后在目标3中,我们将使用敲除小鼠和来自这些小鼠的组织中的生物测定来确定GPR40和GPR120在体内介导PAHSA生物学效应中的作用。药物进入临床需要明确的作用机制,PAHSA靶向两种强烈追求的抗糖尿病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目标筛选,因为PAHSA可能有其他受体或途径。目标3中获得的数据的组合将提供对GPR40、GPR120和其他PAHSA靶点对体内PAHSA生物学的贡献的全面理解。该申请将提供将PAHSA或PAHSA类似物开发成新型抗糖尿病治疗剂所需的结构、药代动力学、毒理学和机理数据。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

BARBARA B. KAHN其他文献

BARBARA B. KAHN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('BARBARA B. KAHN', 18)}}的其他基金

Metabolic Physiology and Energy Balance Core
代谢生理学和能量平衡核心
  • 批准号:
    10586204
  • 财政年份:
    2023
  • 资助金额:
    $ 90.31万
  • 项目类别:
Mechanisms for regulation of a novel class of anti-diabetic lipids
一类新型抗糖尿病脂质的调节机制
  • 批准号:
    10378154
  • 财政年份:
    2016
  • 资助金额:
    $ 90.31万
  • 项目类别:
Regulation of the biosynthesis of a novel class of anti-diabetic lipids
一类新型抗糖尿病脂质生物合成的调节
  • 批准号:
    9895741
  • 财政年份:
    2016
  • 资助金额:
    $ 90.31万
  • 项目类别:
Mechanisms for regulation of a novel class of anti-diabetic lipids
一类新型抗糖尿病脂质的调节机制
  • 批准号:
    10609856
  • 财政年份:
    2016
  • 资助金额:
    $ 90.31万
  • 项目类别:
Metabolic effects of adipose lipogenesis
脂肪脂肪生成的代谢作用
  • 批准号:
    8460669
  • 财政年份:
    2013
  • 资助金额:
    $ 90.31万
  • 项目类别:
Metabolic effects of adipose lipogenesis
脂肪脂肪生成的代谢作用
  • 批准号:
    8626395
  • 财政年份:
    2013
  • 资助金额:
    $ 90.31万
  • 项目类别:
Metabolic effects of adipose lipogenesis
脂肪脂肪生成的代谢作用
  • 批准号:
    8816092
  • 财政年份:
    2013
  • 资助金额:
    $ 90.31万
  • 项目类别:
INTERPLAY OF TRANSTHYRETIN AND RETINOL BINDING PROTEIN IN TYPE 2 DIABETES
转甲状腺素蛋白和视黄醇结合蛋白在 2 型糖尿病中的相互作用
  • 批准号:
    8365542
  • 财政年份:
    2011
  • 资助金额:
    $ 90.31万
  • 项目类别:
INTERPLAY OF TRANSTHYRETIN AND RETINOL BINDING PROTEIN IN TYPE 2 DIABETES
转甲状腺素蛋白和视黄醇结合蛋白在 2 型糖尿病中的相互作用
  • 批准号:
    8170910
  • 财政年份:
    2010
  • 资助金额:
    $ 90.31万
  • 项目类别:
Metabolic Physiology Core
代谢生理学核心
  • 批准号:
    7925277
  • 财政年份:
    2010
  • 资助金额:
    $ 90.31万
  • 项目类别:

相似国自然基金

相似海外基金

Recruitment of brown adipocytes in visceral white adipose tissue by fibroblast growth factor 8b
成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
  • 批准号:
    321208980
  • 财政年份:
    2016
  • 资助金额:
    $ 90.31万
  • 项目类别:
    Research Grants
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8827438
  • 财政年份:
    2014
  • 资助金额:
    $ 90.31万
  • 项目类别:
Induction of brown-like adipocytes in white adipose tissue by food-derived factors
食物源性因子在白色脂肪组织中诱导棕色样脂肪细胞
  • 批准号:
    26450168
  • 财政年份:
    2014
  • 资助金额:
    $ 90.31万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
WAT-on-a-chip - Development of a micofluidic, microphysiologic in vitro adipose tissue model for high-throughput drug screening based on hiPSC-derived adipocytes.
WAT-on-a-chip - 开发微流体、微生理体外脂肪组织模型,用于基于 hiPSC 衍生脂肪细胞的高通量药物筛选。
  • 批准号:
    257256526
  • 财政年份:
    2014
  • 资助金额:
    $ 90.31万
  • 项目类别:
    Research Fellowships
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8828181
  • 财政年份:
    2013
  • 资助金额:
    $ 90.31万
  • 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8520690
  • 财政年份:
    2013
  • 资助金额:
    $ 90.31万
  • 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8629741
  • 财政年份:
    2013
  • 资助金额:
    $ 90.31万
  • 项目类别:
Effect of exercise training on formation of brite adipocytes within white adipose tissue
运动训练对白色脂肪组织内脂肪细胞形成的影响
  • 批准号:
    23700778
  • 财政年份:
    2011
  • 资助金额:
    $ 90.31万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Investigation for the mechanisms of the emergence of brown adipocytes in white adipose tissue
白色脂肪组织中棕色脂肪细胞出现机制的研究
  • 批准号:
    21780261
  • 财政年份:
    2009
  • 资助金额:
    $ 90.31万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
LOUISIANA COBRE: P1: INDUCE THERMOGENIC BROWN ADIPOCYTES IN WHITE ADIPOSE TISSUE
路易斯安那 COBRE:P1:在白色脂肪组织中诱导产热棕色脂肪细胞
  • 批准号:
    7610781
  • 财政年份:
    2007
  • 资助金额:
    $ 90.31万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了