Structure and function of integrins in the kidney

肾脏整合素的结构和功能

基本信息

  • 批准号:
    9354435
  • 负责人:
  • 金额:
    $ 23.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-06-01 至 2020-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): In multicellular organisms, a family of tightly regulated cell adhesion receptors called integrins mediates communication among cells and between cells and their extracellular matrices. Impaired regulation of integrins leads to many pathologies, which in the adult kidney include inflammatory, autoimmune and thrombotic disorders, making integrins important therapeutic targets. Indeed FDA-approved peptidomimetics, synthetic small molecules and monoclonal antibodies (mAbs) are being used to treat thrombotic and autoimmune diseases, and more recently, mAbs targeting αVβ3 have been shown to prevent atherosclerosis, diabetic nephropathy and systemic sclerosis in animal models. The anti-integrin peptidomimetics and synthetic small molecule drugs in current use are patterned after the prototypical integrin binding Arg-Gly-Aps motif in ligands. Their parenteral use has caused serious adverse outcomes in treated patients, and clinical trials using these ligand-mimetics as oral drugs to prevent thrombosis have failed due to unexpected patient death of paradoxical thrombosis. Subsequent biochemical and structural studies showed that these drugs act as partial agonists, i.e. they induce the conformational changes in the integrin produced by binding of physiologic macromolecular ligands. This partial agonism has contributed to the unexpected adverse outcomes seen in treated patients. Hence the need for a better understanding of structure- activity relationships in these receptors and for development of "pure" antagonists that lack the partial agonism of the ligand-mimetic compounds in current use. Our recently published studies generated during the current funding period identified an RGD-based "pure" antagonist and revealed the atomic basis for its unexpected mechanism of action. These studies, in addition to new preliminary data, provide a novel path for synthesis of anti-integrin drugs that lack partial agonism, and a basis for understanding structure-function relationships in integrins in more details. Capitalizing on these exciting new developments is the subject of this competing renewal application.
描述(由申请人提供):在多细胞生物体中,一个被称为整联蛋白的严格调节的细胞粘附受体家族介导细胞之间以及细胞与其细胞外基质之间的通信。整合素调节受损导致许多病理,其在成人肾脏中包括炎性、自身免疫性和血栓性疾病,使得整合素成为重要的治疗靶标。事实上,FDA批准的肽模拟物、合成小分子和单克隆抗体(mAb)正被用于治疗血栓形成和自身免疫性疾病,并且最近,靶向αVβ3的mAb已显示出在动物模型中预防动脉粥样硬化、糖尿病肾病和系统性硬化。目前使用的抗整联蛋白肽模拟物和合成的小分子药物在配体中的原型整联蛋白结合Arg-Gly-Aps基序之后被图案化。它们的肠胃外使用在治疗的患者中引起了严重的不良后果,并且使用这些配体模拟物作为口服药物来预防血栓形成的临床试验由于反常血栓形成的意外患者死亡而失败。随后的生物化学和结构研究表明,这些药物作为部分激动剂,即它们诱导通过结合生理大分子配体产生的整合素的构象变化。这种部分激动作用导致了在治疗患者中观察到的意外不良结局。因此,需要更好地了解这些受体的结构-活性关系,并开发“纯”拮抗剂, 缺乏目前使用的配体模拟化合物的部分激动作用。我们最近发表的研究在目前的资助期间产生的确定了一个基于RGD的“纯”拮抗剂,并揭示了其意外的作用机制的原子基础。这些研究,除了新的初步数据,提供了一种新的途径,合成抗整合素药物,缺乏部分激动剂,并在更详细地了解整合素的结构-功能关系的基础。利用这些令人兴奋的新发展是这个竞争性续期申请的主题。

项目成果

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会议论文数量(0)
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M. AMIN ARNAOUT其他文献

M. AMIN ARNAOUT的其他文献

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{{ truncateString('M. AMIN ARNAOUT', 18)}}的其他基金

Targeting innate immunity for induction of robust renal allograft tolerance
针对先天免疫诱导强大的肾同种异体移植耐受
  • 批准号:
    10622050
  • 财政年份:
    2023
  • 资助金额:
    $ 23.55万
  • 项目类别:
Effects of combining anti-CD40 and anti-CD11b mAb107 on survival of pig kidney xenografts in cynomolgus monkeys
抗CD40和抗CD11b mAb107联合使用对食蟹猴猪肾异种移植物存活的影响
  • 批准号:
    10425736
  • 财政年份:
    2022
  • 资助金额:
    $ 23.55万
  • 项目类别:
Effects of combining anti-CD40 and anti-CD11b mAb107 on survival of pig kidney xenografts in cynomolgus monkeys
抗CD40和抗CD11b mAb107联合使用对食蟹猴猪肾异种移植物存活的影响
  • 批准号:
    10618872
  • 财政年份:
    2022
  • 资助金额:
    $ 23.55万
  • 项目类别:
Platelet alphaIIbbeta3 activation and its therapeutic targeting
血小板αIIbbeta3激活及其治疗靶向
  • 批准号:
    10469477
  • 财政年份:
    2019
  • 资助金额:
    $ 23.55万
  • 项目类别:
Platelet alphaIIbbeta3 activation and its therapeutic targeting
血小板αIIbbeta3激活及其治疗靶向
  • 批准号:
    10251142
  • 财政年份:
    2019
  • 资助金额:
    $ 23.55万
  • 项目类别:
Platelet alphaIIbbeta3 activation and its therapeutic targeting
血小板αIIbbeta3激活及其治疗靶向
  • 批准号:
    10004711
  • 财政年份:
    2019
  • 资助金额:
    $ 23.55万
  • 项目类别:
Role of integrin CD11b in delayed graft function and allorejection
整合素 CD11b 在移植物功能延迟和同种异体排斥中的作用
  • 批准号:
    9809349
  • 财政年份:
    2019
  • 资助金额:
    $ 23.55万
  • 项目类别:
Identification of Novel integrin antagonists
新型整合素拮抗剂的鉴定
  • 批准号:
    8355238
  • 财政年份:
    2012
  • 资助金额:
    $ 23.55万
  • 项目类别:
Identification of Novel integrin antagonists
新型整合素拮抗剂的鉴定
  • 批准号:
    8549221
  • 财政年份:
    2012
  • 资助金额:
    $ 23.55万
  • 项目类别:
Structure and Function of Integrins in the Kidney
肾脏中整合素的结构和功能
  • 批准号:
    10375579
  • 财政年份:
    2010
  • 资助金额:
    $ 23.55万
  • 项目类别:

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