LRP/RanBP9 Pathway in Alzheiimer's Disease Pathogenesis

LRP/RanBP9 通路在阿尔茨海默病发病机制中的作用

• 批准号: 8133969
• 负责人: David E Kang
• 金额: $ 6.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133969
• 关键词: Abeta synthesis; Adaptor Signaling Protein; Adverse effects; Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Axon; Binding Proteins; Biochemical; Biological; Brain; C-terminal; Characteristics; Collaborations; Complement; Complex; Cultured Cells; Cytoplasmic Tail; Disease; Funding; Generations; Genotype; Goals; Hybrids; Imaging Techniques; LDL-Receptor Related Protein 1; Late Onset Alzheimer Disease; Learning; Length; Lesion; Ligand Binding Domain; Ligands; Light; Lipoprotein Receptor; Macroglobulins; Mediating; Metabolism; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurosciences; Pathogenesis; Pathway interactions; Patients; Peptides; Peripheral; Phage Display; Phase; Play; Principal Investigator; Process; Production; Protein Binding; Proteins; Regulation; Research; Research Technics; Research Training; Role; Running; SNAPIN gene; Screening procedure; Signal Pathway; Sorting - Cell Movement; Techniques; Therapeutic; Therapeutic Uses; Time; Training; Transgenic Mice; Transmembrane Domain; Work; Yeasts; amyloid precursor protein processing; base; career; design; in vivo; inhibitor/antagonist; insight; myelination; new therapeutic target; notch protein; novel strategies; protein aminoacid sequence; protein function; protein metabolism; protein transport; ran GTP-Binding Protein; secretase; tau Proteins; tool; trafficking

DESCRIPTION (provided by applicant): I am a principal investigator with 15 years of training and research in Alzheimer's disease and neurodegeneration. The long-term goals for my research career are to 1) clearly understand the molecular and cellular mechanisms that drive the accumulation of amyloid beta protein in Alzheimer's disease, 2) mechanistically define signaling pathways that mediate and/or potentiate the deleterious effects of pathological lesions in neurodegenerative diseases, and 3) identify novel therapeutic targets and approaches to treat neurodegeneration. Using a yeast 2-hybrid screen, we recently identified 2 new proteins, RanBP9 and Snapin, which interact with a previously uncharacterized domain of LRP cytoplasmic tail (CST) and modulate APP processing. Our working hypothesis is that the LRP-C37 domain and its interacting proteins, in particular RanBP9, play important roles in APP trafficking and Abeta generation. My short-term goals relevant for this K02 application relate to the role of the LRP/RanBP9 pathway in the regulation of APP/Abeta metabolism. Specifically, they are to 1) determine the mechanistic basis of LRP-C37 domain of LRP in APP trafficking and Abeta generation, 2) study the role of Snapin and RanBP9 in LRP / APP trafficking and Abeta production in cultured cells and in vivo, and 3) identify peptide sequences potentially capable of blocking the pro-amyloidogenic action of RanBP9 by phage display screening. In addition, I would like to take this opportunity to significantly further my repertoire of research techniques by taking the time to attend training courses and initiate collaborations with experts in research techniques I aspire to learn, especially in sophisticated imaging techniques, embryological, and advanced neuroscience techniques. These research tools will not only complement the currently funded research proposed here but will also help to solve future research challenges in the next phase of my career. RELEVANCE: As the major defining characteristic of Alzheimer's disease (AD) brains is the excessive accumulation of a toxic protein called Abeta, understanding the biological mechanisms by which Abeta is generated is critical for designing effective therapeutic strategies for AD. This proposal is aimed at providing a novel approach for therapeutically targeting Abeta in AD by characterizing the LRP / RanBP9 pathway.

描述（由申请人提供）：我是一名首席研究员，对阿尔茨海默氏病和神经变性的培训和研究进行了15年的培训和研究。我的研究职业的长期目标是1）清楚地了解驱动阿尔茨海默氏病中淀粉样蛋白β蛋白积累的分子和细胞机制，2）机械师定义了介导和/或有效的信号传导途径在神经退行性疾病中，3）确定治疗神经变性的新型治疗靶标和方法。我们使用酵母2杂交屏幕，最近鉴定了2种新蛋白Ranbp9和Snapin，它们与以前未经表征的LRP细胞质尾巴（CST）和调制App Processing相互作用。我们的工作假设是，LRP-C37结构域及其相互作用的蛋白质，尤其是RANBP9，在应用程序运输和Abeta生成中起着重要作用。我与此K02应用相关的短期目标与LRP/RANBP9途径在APP/ABETA代谢调节中的作用有关。具体而言，它们是1）确定LRP在App Fracking和Abeta Generation中LRP-C37域的机理基础，2）研究Snapin和Ranbp9在LRP / App Traking和Abeta生产中的作用3）确定通过噬菌体显示筛选来阻止RANBP9的淀粉样蛋白生成作用的肽序列。此外，我想借此机会通过抽出时间参加培训课程并与研究技术的专家进行合作，从而大大进一步进一步进一步，尤其是在精致的成像技术，胚胎学和高级神经科学方面的合作。技术。这些研究工具不仅将补充此处提出的当前资助的研究，而且还将有助于解决我职业生涯的下一阶段的未来研究挑战。 相关性：由于阿尔茨海默氏病（AD）大脑的主要定义特征是一种称为Abeta的有毒蛋白的过度积累，因此了解生成Abeta生成的生物学机制对于设计有效的AD治疗策略至关重要。该建议旨在通过表征LRP / RANBP9途径来提供一种新颖的方法来靶向AD的ABETA。