Center for Pediatric Research

儿科研究中心

基本信息

批准号：
10853625
负责人：
DAVID A. PEARCE
金额：
$ 9.3万
依托单位：
SANFORD RESEARCH/USD
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10853625
关键词：
Acute Address Affect Biochemical Biochemistry Biological CRISPR/Cas technology Cell Maintenance Cell model Cell physiology Cells Cellular Membrane Cellular Structures Centers of Research Excellence Chemicals Child Child Development Childhood Cholesterol Cholesterol Synthesis Inhibition Clathrin Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Compensation Complex Core Facility Critical Pathways Data Defect Development Developmental Delay Disorders Disease Disease model Disparate Dissection Endocytosis Enzymes Exhibits Extracellular Space Fostering Genes Genetic Genome Goals Health Human Imaging Techniques Immune Impairment Individual Institution Knowledge Laboratories Life Lipids Macrophage Mammalian Cell Mammals Mediating Membrane Membrane Biology Membrane Proteins Metabolism Microglia Modeling Molecular Target Mutation Normal Cell Nutrient Pathogenesis Pathologic Pathway interactions Patients Pediatric Research Phagocytosis Phenotype Phosphatidylinositols Phospholipids Process Proteins Publications Publishing Receptor Inhibition Regulation Research Research Personnel Role Science Signal Pathway Signal Transduction Site South Dakota Sterols Testing Tissues Training Translational Research United States National Institutes of Health Universities Validation Viral Work cell growth regulation cell type cholesterol biosynthesis clinical effect clinical phenotype clinically relevant combinatorial design disability follow-up improved innovation insight interest macromolecule malformation multidisciplinary novel receptor reconstitution recruit superresolution imaging therapeutic development trafficking translational applications translational potential uptake whole genome

项目摘要

PROJECT SUMMARY The goal of the Center for Pediatric Research established at Sanford Research was to establish a multidisciplinary center to support translational research being performed by investigators with broad interests in pediatric disease. The proposed supplement will provide support for a new collaborative project encompassing the laboratories of three separate IDeA institution investigators, including one former project leader from our COBRE (Dr. Kevin Francis) and two investigators currently supported by a separate COBRE established at South Dakota State University (Dr. Natalie Thiex and Dr. Brandon Scott). The project itself is scientifically innovative, expanding upon a recent publication authored by two of the investigators’ laboratories, addressing a novel role for defects in endocytosis within pediatric disorders of cholesterol synthesis. The work proposed has the potential to provide significant contributions to these poorly characterized pediatric diseases. In addition, this project epitomizes a team science-based approach by combining overlapping interests with distinct expertise across each laboratory while utilizing COBRE-supported core facilities. While all three investigators have common interests in lipid regulation of cellular function, their complementary expertise and training will allow a thorough dissection and understanding of the impact of sterol biochemistry on endocytic trafficking with direct relevance to disorders of cholesterol synthesis. Eight known diseases are caused by genetic disruption of cholesterol synthesis enzymes, resulting in loss of cholesterol content and the aberrant expression of cholesterol precursor molecules. These disorders arise during childhood and create life-altering disabilities within affected individuals due to both developmental and functional deficits within affected children. Though these diseases share broad commonalities associated with developmental delay, biochemical deficits, and tissue malformations, disease pathogenesis varies greatly across individuals and thus therapeutic development for these children has been limited. While disease- associated deficits are likely due to combinatorial changes in cell signaling, membrane structure, and cell- specific processes, the precise effects of sterol biochemical changes and the mechanisms whereby cholesterol vs disease-associated sterols regulate membrane biology remain unresolved. Therefore, delineating how clinically relevant sterol biochemistry affects basic cellular functions with disease relevance constitutes an unmet scientific need for affected children. The synthesis of cholesterol from sterol precursors is a highly regulated pathway critical to cell structure and signaling across mammalian cells and tissues. Our recent work detailed a critical role for conserved sterol structural features and expression levels in the regulation of the critical cargo internalization mechanism clathrin-mediated endocytosis (CME). As the intracellular delivery of molecules is vital to maintenance of cell signaling, function, and health, fully defining the impact of disease-associated sterol biochemistry on membrane biology represents a novel biological mechanism which could help explain differences in the pathogenesis of cholesterol synthesis disorders and identify targetable, functional pathways to improve cell health. For this proposal, we will utilize disease-relevant cellular models to test the hypothesis that cellular membranes require highly specific sterol biochemistry to promote functional internalization of macromolecules and lipid ordering. In Aim 1, we will first define the role of clinically relevant sterols on functional internalization of macromolecules, differentiating between disease-specific impacts and defining cell signaling changes specific to immune cells of interest. In Aim 2, we will determine the mechanisms whereby disease-relevant sterol biochemical changes regulate membrane function through super resolution imaging of endocytic processes and recruitment of PtdIns species to endocytic sites. In Aim 3, we will utilize a CRISPR-based whole genome screen and follow-up validation to delineate genes, signaling pathways, and cellular processes that contribute to or compensate for endocytic defects resulting from cholesterol synthesis disruption. In summary, these studies constitute a novel proposal detailing how sterol metabolism regulates mammalian membrane biology with direct correlation to cell function and rare pediatric diseases. We anticipate completion of the proposed work will provide important insight into the regulation of endocytosis by sterol biochemistry with high relevance to this group of lethal pediatric disorders. Additionally, continued support will further foster this cross-institute collaboration and allow the supported investigators to extend these studies in the form of a multi-PI NIH application upon completion of the work proposed.

项目概要桑福德研究中心儿科研究中心的目标是建立一个多学科中心支持具有广泛兴趣的研究人员进行的转化研究拟议的补充将为一个新的合作项目提供支持。包括三名独立 IDeA 机构研究人员的实验室，其中包括一名前项目人员我们 COBRE 的领导者（Kevin Francis 博士）和两名研究人员目前由单独的 COBRE 支持该项目本身是在南达科他州立大学建立的（Natalie Thiex 博士和 Brandon Scott 博士）。科学创新，扩展了两个研究人员实验室最近发表的出版物，这项工作探讨了内吞作用缺陷在儿科胆固醇合成疾病中的新作用。所提出的方案有可能对这些特征不明的儿科疾病做出重大贡献。此外，该项目体现了一种基于科学的团队方法，将重叠的兴趣与每个实验室都有独特的专业知识，同时利用 COBRE 支持的核心设施。研究人员对细胞功能的脂质调节有着共同的兴趣，他们的专业知识互补，培训将有助于彻底剖析和理解甾醇生物化学对内吞的影响与胆固醇合成障碍直接相关的贩运。八种已知疾病是由胆固醇合成酶的基因破坏引起的，导致胆固醇合成酶的丧失胆固醇含量和胆固醇前体分子的异常表达会产生这些疾病。由于发育和尽管这些疾病具有与相关的广泛共性，但受影响儿童的功能缺陷。发育迟缓、生化缺陷和组织畸形，疾病发病机制差异很大个体之间的差异，因此这些儿童的治疗发展受到限制。相关的缺陷可能是由于细胞信号传导、膜结构和细胞- 具体过程、甾醇生化变化的精确影响以及胆固醇的机制与疾病相关的甾醇调节膜生物学的问题仍然悬而未决。临床相关的甾醇生物化学影响与疾病相关的基本细胞功能受影响儿童的科学需求未得到满足。从甾醇前体合成胆固醇是一条高度调控的途径，对细胞结构和细胞结构至关重要。我们最近的工作详细介绍了保守甾醇的关键作用。关键货物内化机制调节的结构特征和表达水平网格蛋白介导的内吞作用（CME），因为分子的细胞内递送对于细胞的维持至关重要。信号、功能和健康，全面定义与疾病相关的甾醇生物化学对膜生物学代表了一种新的生物机制，可以帮助解释胆固醇合成障碍的发病机制，并确定可改善细胞的有针对性的功能途径对于这项提议，我们将利用与疾病相关的细胞模型来检验细胞的假设。膜需要高度特异性的甾醇生物化学来促进大分子的功能内化在目标 1 中，我们将首先定义临床相关甾醇对功能内化的作用。大分子，区分疾病特异性影响并定义细胞信号传导变化在目标 2 中，我们将确定与疾病相关的机制。甾醇生化变化通过内吞超分辨率成像调节膜功能在目标 3 中，我们将利用基于 CRISPR 的整体。基因组筛选和后续验证，以描绘基因、信号通路和细胞过程有助于或补偿由胆固醇合成破坏引起的内吞缺陷。总之，这些研究构成了一项新颖的提议，详细说明了甾醇代谢如何调节哺乳动物我们预计将完成与细胞功能和罕见儿科疾病直接相关的膜生物学。所提出的工作将为甾醇生物化学对内吞作用的调节提供重要的见解此外，与这组致命的儿科疾病高度相关，持续的支持将进一步促进这一点。跨机构合作，并允许支持的研究人员以完成建议的工作后，进行多 PI NIH 申请。

项目成果

期刊论文数量（108）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SUSD2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance.

高级别浆液性卵巢癌中的 SUSD2 表达与患者生存率增加和间皮清除缺陷相关。

DOI：
10.1038/oncsis.2016.64
发表时间：
2016-10-24
期刊：
ONCOGENESIS
影响因子：
6.2
作者：
Sheets, J. N.;Iwanicki, M.;Liu, J. F.;Howitt, B. E.;Hirsch, M. S.;Gubbels, J. A. A.;Drapkin, R.;Egland, K. A.
通讯作者：
Egland, K. A.

Rational Design of a Cu Chelator That Mitigates Cu-Induced ROS Production by Amyloid Beta.

DOI：
10.1002/cbic.202100485
发表时间：
2022-02-16
期刊：
CHEMBIOCHEM
影响因子：
3.2
作者：
Mitra, Suchitra;Talukdar, Kallol;Prasad, Pallavi;Misra, Sandeep K.;Khan, Shabana;Sharp, Joshua S.;Jurss, Jonah W.;Chakraborty, Saumen
通讯作者：
Chakraborty, Saumen

Concise Review: Fat and Furious: Harnessing the Full Potential of Adipose-Derived Stromal Vascular Fraction.