课题基金 / 基金详情

Chemical Biology to Modulate PCSK9 and Treat Atherosclerosis

Chemical Biology to Modulate PCSK9 and Treat Atherosclerosis
调节 PCSK9 和治疗动脉粥样硬化的化学生物学
批准号:
10598882
负责人:
John S Chorba
金额:
$9.34万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-07-01 至 2026-06-30

项目摘要

项目成果

John S Chorba的其他基金

相似基金

相关文献

中文摘要
翻译
专利授权项目概要/摘要 血清低密度脂蛋白(LDL)导致动脉粥样硬化性心脏病。作为LDL受体(LDLR), 肝脏从血液中清除LDL,上调肝脏LDLR可降低LDL和心血管事件。的 自切割蛋白酶PCSK 9(前蛋白转化酶枯草杆菌蛋白酶/kexin 9型)是一种经验证的治疗靶点;它 伴随LDLR的溶酶体降解,下调其功能。抗PCSK 9抗体较低 低密度脂蛋白和改善临床结果,但成本和管理要求说明需要替代品。 肝脏靶向siRNA也能有力地降低LDL,但与耐受性良好的遗传变异不同,它能去除所有的LDL。 PCSK 9的细胞,提高了安全性问题。虽然PCSK 9对肝脏的作用机制是 LDLR已被充分理解,但其在该经典途径之外的功能尚不清楚。因此整体 我们建议的目标是开发生物化学工具来机械地剖析PCSK 9的生物学,以便 1)预测当前抗PCSK 9疗法的长期效果,2)开发以下方面的原理证明: 新的PCSK 9靶向策略。为此,我们已经确定了三种有希望的先导化合物, 特异性靶向细胞内PCSK 9。这些化合物既抑制PCSK 9自身蛋白水解, 上调LDLR表达。在目标1中,我们将对这些化合物进行化学优化,确认其机理, 基于其作用,并在体内模型中验证其对PCSK 9和LDLR的功能。这将 建立新的化学探针,可用于研究细胞内PCSK 9鲜为人知的功能, 以及作为上调LDLR的替代小分子治疗剂的起始点。我们 还发现其他因子,包括硫酸乙酰肝素蛋白聚糖(HSPG),与PCSK 9相互作用 以调节其向溶酶体的运输,这表明在该途径中存在另外的药物靶点。在 目的2,我们将评估HSPG作为PCSK 9内吞运输所需介质的贡献, 体外和人体LDLR下调。这些结果将阐明, 已经批准的疗法,可以重新用于抑制PCSK 9功能。在目标3中,我们将确定和 通过无偏倚的全基因组CRISPR验证PCSK 9内吞运输的未知调节因子 干扰屏这些结果将有助于机械地定义PCSK 9如何被运输到溶酶体, 为为什么PCSK 9只影响某些组织提供了答案,并提供了潜在的新的治疗靶点, 预期具有与PCSK 9本身相似的治疗窗。总的来说,我们希望我们的研究能够 提供关于长期PCSK 9抑制安全性的关键信息,为新型治疗奠定基础, 并确定新的抗动脉粥样硬化治疗靶点。
英文摘要
PARENT GRANT PROJECT SUMMARY/ABSTRACT Serum low-density lipoprotein (LDL) causes atherosclerotic heart disease. As the LDL receptor (LDLR) on the liver clears LDL from the blood, upregulating hepatic LDLR reduces both LDL and cardiovascular events. The self-cleaving protease PCSK9 (proprotein convertase subtilisin/kexin type 9) is a validated therapeutic target; it chaperones the LDLR for lysosomal degradation, downregulating its function. Antibodies against PCSK9 lower LDL and improve clinical outcomes, but cost and administration requirements illustrate a need for alternatives. Liver-targeted siRNA also robustly lowers LDL, but unlike the well-tolerated genetic variants, it removes all PCSK9 from the cell, raising safety concerns. Though the mechanistic basis for PCSK9's effect on the hepatic LDLR is well understand, its functions outside this canonical pathway are less clear. Therefore, the overall goal of our proposal is to develop biochemical tools to mechanistically dissect the biology of PCSK9, so as to 1) anticipate the long-term effects of current anti-PCSK9 therapies and 2) develop the proofs-of-principle for novel PCSK9-targeting strategies. To this end, we have identified three promising lead compounds that specifically target intracellular PCSK9. These compounds both inhibit PCSK9 self-proteolysis and also upregulate LDLR expression. In Aim 1, we will chemically optimize these compounds, confirm the mechanistic basis of their effects, and validate their function on PCSK9 and the LDLR in an in vivo model. This will establish novel chemical probes which can be used to study the poorly known function of intracellular PCSK9, as well as serve as the starting point for an alternative small molecule therapeutic to upregulate the LDLR. We have also found that additional factors, including heparan sulfate proteoglycans (HSPGs), interact with PCSK9 to modulate its trafficking to the lysosome, suggesting that there are additional drug targets in this pathway. In Aim 2, we will evaluate the contribution of HSPGs as mediators of the PCSK9 endocytic trafficking required for LDLR downregulation, both in vitro and in the human. These results will elucidate whether heparins, which are already approved therapies, could be repurposed to inhibit PCSK9 function. In Aim 3, we will identify and validate as yet unknown regulators of PCSK9 endocytic trafficking via an unbiased, genome-wide CRISPR interference screen. These results will help mechanistically define how PCSK9 is trafficked to the lysosome, provide answers to why PCSK9 only affects certain tissues, and offer potential novel therapeutic targets which would be anticipated to have similar therapeutic windows to PCSK9 itself. Overall, we expect our study to provide key information on the safety of long-term PCSK9 inhibition, lay the groundwork for novel treatments, and identify new therapeutic targets against atherosclerosis.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Small molecule allosteric inhibitors of PCSK9 processing to phenocopy cardioprotective genetic variants.
CSDE1 as a Post Transcriptional Regulator of the LDLR - Diversity Supplement
CSDE1 as a Post Transcriptional Regulator of the LDLR
Sequence Specific Inhibition of Protein Translation
海外基金