Fis1 Regulation of Mitochondrial Fission

Fis1 线粒体裂变的调节

• 批准号: 10582168
• 负责人: R Blake Hill
• 金额: $ 4.4万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582168
• 关键词: Administrative Supplement; Aging; Alzheimer' s Disease; Cells; Cellular Structures; Cessation of life; Data Analyses; Data Collection; Daughter; Diabetes Mellitus; Disease; Equilibrium; Event; Goals; Heart Diseases; Impairment; Lead; Life; Life Cycle Stages; Machine Learning; Malignant Neoplasms; Metabolic stress; Microscope; Microscopic; Mitochondria; Modeling; Myocardial Infarction; Neonatal; Neurodegenerative Disorders; Parkinson Disease; Pathologic; Power Plants; Process; Proteins; Recovery; Regulation; Stroke; Syndrome; Testing; Work; human disease; instrumentation; mutant; normal aging; novel therapeutic intervention; screening; small molecule; tool

The goal of this administrative supplement request is to provide needed upgrades to a Nikon spinning disc confocal microscope screening for studies on mitochondrial fission proteins for R01GM067180. Altered mitochondrial fission has severe consequences even death. Yet the reasons for this are unknown. It is postulated that the mitochondria have their own lifecycle that involves fission of unhealthy mitochondria to remove them. In this model, the proper balance of fission is critical: either excess or impaired fission result in unhealthy mitochondria. This model is compelling because it explains how alterations in fission can cause or contribute to many fundamentally different diseases including recovery from heart attack and stroke, increased metabolic stress from diabetes, normal aging, and neurodegenerative diseases such as Parkinson's and Alzheimer's disease. To determine this, we have generated several mutants, many of which are pathological. We are testing hypotheses by determining how these mutants impact biomolecular interactions inside cells. The requested instrumentation will greatly accelerate our work as it allows for faster data collection and analysis including the use of cutting- edge machine learning tools. Detailed microscopic information will provide a better understanding of the protein machinery and how it works, which will identify key points of regulation that may be targeted with small molecules to inhibit, and activate, fission. The discovery of such molecules may ultimately lead to treatments for diseases in which enhanced, or impaired, fission is central.

此行政补充请求的目标是为尼康提供所需的升级 旋转盘共聚焦显微镜筛选线粒体裂变蛋白研究 R01GM067180。线粒体裂变的改变会带来严重的后果，甚至死亡。然而 其原因尚不清楚。据推测，线粒体有自己的生命周期 涉及不健康线粒体的裂变以去除它们。在这个模型中，适当的平衡 裂变至关重要：裂变过多或受损都会导致线粒体不健康。这个型号是 引人注目，因为它解释了裂变的改变如何导致或促成许多 根本不同的疾病，包括从心脏病发作和中风中恢复过来，增加 糖尿病、正常衰老和神经退行性疾病（例如 帕金森病和阿尔茨海默病。为了确定这一点，我们产生了几个突变体， 其中许多是病态的。我们正在通过确定这些突变体如何 影响细胞内生物分子的相互作用。所要求的仪器将极大地 加速我们的工作，因为它可以更快地收集和分析数据，包括使用切割- 边缘机器学习工具。详细的微观信息将有助于更好地理解 蛋白质机制及其工作原理，这将确定可能的调控关键点 以小分子为目标来抑制和激活裂变。此类分子的发现 可能最终导致以增强或受损裂变为核心的疾病的治疗。

项目成果

Cytosolic domain of the human mitochondrial fission protein fis1 adopts a TPR fold.

人线粒体裂变蛋白 fis1 的胞质结构域采用 TPR 折叠。

• 发表时间: 2004-01-01
• 影响因子: 2.9
• 作者: Dohm, Julie A;Lee, Sarah J;Hardwick, J Marie;Hill, R Blake;Gittis, Apostolos G
• 通讯作者: Gittis, Apostolos G

The C. elegans B-cell lymphoma 2 (Bcl-2) homolog cell death abnormal 9 (CED-9) associates with and remodels LIPID membranes.

线虫 B 细胞淋巴瘤 2 (Bcl-2) 同源细胞死亡异常 9 (CED-9) 与 LIPID 膜相关并重塑。

• 发表时间: 2011-01
• 作者: Tan, Frederick J;Zuckerman, Jonathan E;Wells, Robert C;Hill, R Blake
• 通讯作者: Hill, R Blake

A Targeted Mutation Identified through pKa Measurements Indicates a Postrecruitment Role for Fis1 in Yeast Mitochondrial Fission.

通过 pKa 测量鉴定的靶向突变表明 Fis1 在酵母线粒体裂变中的招募后作用。

• 发表时间: 2016
• 作者: Koppenol;Harwig, Megan Cleland;Posey, Ammon E;Egner, John M;MacKenzie, Kevin R;Hill, R Blake
• 通讯作者: Hill, R Blake

The 1.75 A resolution structure of fission protein Fis1 from Saccharomyces cerevisiae reveals elusive interactions of the autoinhibitory domain.

酿酒酵母裂变蛋白 Fis1 的 1.75 A 分辨率结构揭示了自抑制结构域难以捉摸的相互作用。

• 发表时间: 2011-11-01
• 作者: Tooley, James E;Khangulov, Victor;Lees, Jonathan P B;Schlessman, Jamie L;Bewley, Maria C;Heroux, Annie;Bosch, Jurgen;Hill, R Blake
• 通讯作者: Hill, R Blake

Removal of a consensus proline is not sufficient to allow tetratricopeptide repeat oligomerization.

共有脯氨酸的去除不足以允许四肽重复寡聚化。

• 发表时间: 2017-10
• 作者: Bakkum, Amber L;Hill, R Blake
• 通讯作者: Hill, R Blake