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Neurosteroid Inhibition of Pyroptotic Lysis

神经类固醇抑制焦亡裂解

基本信息

批准号：
10037720
负责人：
Susan Leilani Fink
金额：
$ 19.44万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-25 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10037720
关键词：
Address Affect Allopregnanolone Biological CASP1 gene Cardiovascular Diseases Cell Death Cell Death Process Cell Volumes Cell membrane Cells Cleaved cell Clinical Chemistry Cytolysis Data Development Disease Event Experimental Designs Family Foundations Goals Inflammasome Intervention Ion Channel Libraries Lipid Binding Lipids Membrane Membrane Lipids Membrane Proteins Molecular Myocardial Infarction N-terminal Nerve Degeneration Nervous System Physiology Neurons Pathogenesis Pathology processes Peptide Hydrolases Physiological Positioning Attribute Process Proteins Regulation Role Sepsis Steroids Stroke Structure Structure-Activity Relationship Testing Therapeutic Vertebral column experimental study human disease inhibitor/antagonist innovation lipophilicity mortality nervous system disorder neurosteroids novel novel strategies pregnenolone sulfate prevent programs release factor repaired small molecule

项目摘要

Project Summary Pyroptosis is a program of cell death involved in the pathogenesis of leading global causes of mortality. Caspase-1 family proteases initiate pyroptosis by releasing the pore-forming portion of gasdermin D, which inserts into the plasma membrane leading to cell lysis. Cellular factors released during pyroptotic lysis cause local and systemic pathology, but processes regulating gasdermin D pore formation and lysis are not well understood. We recently identified the neurosteroid pregnenolone sulfate as a novel inhibitor of pyroptotic lysis, but its mechanism of action is not yet known. Neurosteroids including pregnenolone sulfate have a lipophilic backbone and interact with plasma membrane proteins and lipids, suggesting the hypothesis that these molecules may disrupt formation of gasdermin D pores. This proposal aims to understand how pregnenolone sulfate prevents pyroptotic lysis and determine whether other steroids share this activity. Our preliminary data demonstrate that pregnenolone sulfate prevents lysis during pyroptosis without affecting upstream activation of inflammasomes or caspase-1. The experiments outlined in this proposal will test the hypothesis that pregnenolone sulfate affects pore formation during pyroptosis and assess gasdermin D cleavage, plasma membrane localization and oligomerization. We will also address the alternative hypotheses that pregnenolone sulfate may regulate cell volume to prevent lysis or potentiate membrane repair processes. Together, the results of these experiments will inform a precise molecular understanding of the mechanism of action and reveal a novel strategy to disrupt pyroptotic lysis. The steroid backbone is shared by a large number of molecules, each with specific biological activities. Our preliminary data suggest that there may be molecular determinants for steroid inhibition of pyroptotic lysis, as a related steroid demonstrates reduced potency. We will test a rationally selected library of structurally distinct steroids for the ability to prevent pyroptotic lysis. These experiments will determine whether endogenous steroids demonstrate potency consistent with potential physiologic relevance. In addition, these results will identify the structure-activity relationship for inhibition of pyroptotic lysis to facilitate development of potent and specific molecules and define a new paradigm for disease intervention.

项目概要细胞焦亡是一种细胞死亡程序，涉及全球主要死亡原因的发病机制。 Caspase-1 家族蛋白酶通过释放 Gasdermin D 的成孔部分来启动细胞焦亡，该部分插入质膜导致细胞裂解。焦亡裂解过程中释放的细胞因子局部和全身病理学，但调节gasdermin D孔形成和溶解的过程并不好明白了。我们最近发现神经类固醇孕烯醇酮硫酸盐是一种新型焦亡抑制剂裂解，但其作用机制尚不清楚。包括孕烯醇酮硫酸盐在内的神经类固醇具有亲脂性主链并与质膜蛋白和脂质相互作用，提出以下假设：这些分子可能会破坏 Gasdermin D 孔的形成。该提案旨在了解如何孕烯醇酮硫酸盐可防止焦亡裂解并确定其他类固醇是否具有这种活性。我们的初步数据表明，孕烯醇酮硫酸盐可防止细胞焦亡过程中的裂解，而不影响炎症小体或 caspase-1 的上游激活。本提案中概述的实验将测试孕烯醇酮硫酸盐影响焦亡过程中孔形成的假设并评估gasdermin D 裂解、质膜定位和寡聚化。我们还将讨论替代假设孕烯醇酮硫酸盐可以调节细胞体积以防止裂解或增强膜修复过程。总之，这些实验的结果将有助于对分子机制的精确理解。行动并揭示了一种破坏焦亡裂解的新策略。类固醇骨架由大量分子共享，每个分子都具有特定的生物活性。我们的初步数据表明，类固醇抑制焦亡裂解可能存在分子决定因素，相关类固醇的效力降低。我们将测试合理选择的结构不同的库类固醇具有防止焦亡溶解的能力。这些实验将确定内源性是否类固醇的效力与潜在的生理相关性一致。此外，这些结果将确定抑制焦亡裂解的结构-活性关系，以促进有效和有效的开发特定分子并定义疾病干预的新范式。