iNOS Aggresome as a Prototype of a Physiologic Aggresome

iNOS Aggresome 作为生理 Aggresome 的原型

• 批准号: 7777826
• 负责人: N. Tony Eissa
• 金额: $ 36.41万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777826
• 关键词: 26S proteasome; Acceleration; Air; Area; Cell Culture Techniques; Cell Nucleus; Cells; Cultured Cells; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Degradation Pathway; Disease; Educational workshop; Electroconvulsive Therapy; Epithelial Cells; Future; Generations; Hand; Heat-Shock Response; Interphase; Interstitial Lung Diseases; Link; Liquid substance; Lung diseases; Mediating; Molecular; Molecular Chaperones; Mutation; National Heart, Lung, and Blood Institute; Nature; Pathogenesis; Pathologic; Pathway interactions; Physiological; Play; Process; Protein C Inhibitor; Proteins; Recommendation; Regulation; Research; Research Personnel; Resort; Role; Staging; Testing; Therapeutic; cell growth regulation; design; human NOS2A protein; inhibitor/antagonist; mutant; programs; protein aggregate; protein misfolding; protein transport; prototype; response

Misfolding of proteins plays an important part in the pathogenesis of several lung diseases. Misfolded and aggregated proteins are handled in the cell through chaperone-mediated refolding, or destroyed by proteasomal degradation. Recent evidence suggests that cells have evolved a third pathway that involves sequestration of misfolded proteins into specialized "holding stations", close to the nucleus, called aggresomes. Recognizing the importance of this topic, the NHLBI convened a workshop to review protein processing related issues. The workshop emphasized the need for understanding the nature and the role of aggresome and the cellular mechanisms of its formation. We have discovered that cells regulate inducible nitric oxide synthase (iNOS) through aggresome formation. This newly discovered iNOS aggresome is the first described occurrence of an aggresome that is not associated with protein misfolding and which we termed "physiologic aggresome". This discovery sets the stage for a unique research opportunity. Study of the physiologic aggresome should reveal a wealth of information regarding how cells regulate proteins through aggresome formation. We hypothesize that: A) iNOS physiologic aggresome shares certain features with what previously described as "pathologic" aggresome associated with misfolded proteins. Thus, pathologic aggresome may merely represent an acceleration of an established physiologic regulatory process. B) The regulation of aggresome formation in cells is linked to cell capacity to degrade proteins in a timely manner. Whenever cells sense that this capacity is likely to be exceeded due to the generation of either a misfolded protein or a large amount of a certain protein, they trigger aggresome formation. The decision of cells to resort to aggresome formation results in specific proteins migrating to participate in the formation and the regulation of the aggresome. To test these hypotheses we propose studies with the following specific aims: 1) Characterization of mechanisms of formation and regulation of iNOS aggresome. 2) Identification of proteins forming iNOS aggresome. 3) Examination of the regulation of iNOS aggresome in cells harboring misfolded mutant proteins related to lung disease such as a1-antitrypsin mutants. The rationale for the proposed studies is that once these mechanisms are understood, they would greatly increase our understanding of cellular handing of misfolded proteins. Future therapeutic strategies can be designed to regulate these cellular responses in disease states.

蛋白质的错误折叠在几种肺部疾病的发病机制中起着重要作用。错误折叠和 聚集的蛋白质在细胞中通过分子伴侣介导的重折叠进行处理，或被 蛋白酶体降解最近的证据表明，细胞已经进化出第三条途径， 将错误折叠的蛋白质隔离到靠近细胞核的专门的“保持站”，称为侵袭体。 认识到这一主题的重要性，NHLBI召开了一个研讨会，审查蛋白质加工相关的 问题.讲习班强调，必须了解侵略者的性质和作用， 其形成的细胞机制。 我们发现细胞通过侵袭素体调节诱导型一氧化氮合酶（iNOS）， 阵这个新发现的iNOS攻击组是第一个描述的攻击组， 与蛋白质错误折叠相关，我们称之为“生理侵略组”。这一发现奠定了 一个独特的研究机会。对生理攻击基因组的研究将揭示大量信息 关于细胞如何通过攻击体的形成来调节蛋白质。 我们假设：A）iNOS生理性攻击组与先前的攻击组共享某些特征， 被描述为与错误折叠的蛋白质相关的“病理性”侵袭体。因此，病理性侵袭可能 仅仅代表了一个已建立的生理调节过程的加速。B）对以下方面的管制 细胞中攻击体的形成与细胞及时降解蛋白质的能力有关。每当细胞 这意味着由于产生错误折叠的蛋白质或大的 一定量的某种蛋白质，它们会触发攻击基因组的形成。细胞诉诸攻击性的决定 形成的结果是特定的蛋白质迁移，参与形成和调节， 咄咄逼人。 为了验证这些假设，我们提出了以下具体目标的研究：1）表征 iNOS攻击体的形成和调控机制。2)形成iNOS的蛋白质的鉴定 咄咄逼人。3)在含有错误折叠突变蛋白的细胞中检查iNOS攻击体的调节 与肺部疾病相关的突变体，如α 1-抗胰蛋白酶突变体。提出研究的理由是，一旦 这些机制被理解，他们将大大增加我们对细胞处理的理解。 错误折叠的蛋白质未来的治疗策略可以被设计为调节这些细胞反应， 疾病状态。