ROLE OF LRP IN CELLULAR SIGNALING AND APP PROCESSING

LRP 在蜂窝信号传输和应用程序处理中的作用

• 批准号: 7675992
• 负责人: Joseph D. Buxbaum
• 金额: $ 30.7万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7675992
• 关键词: Abeta clearance; Affect; Alzheimer' s Disease; Amyloid Proteins; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Binding; Biochemical; Biochemical Genetics; Brain; Catabolism; Cell physiology; Cells; Class; Collaborations; Complex; Cytoplasmic Tail; DNA Sequence; Disease; Disruption; Endopeptidases; ErbB4 gene; Extracellular Domain; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Integral Membrane Protein; Knock-out; Ligands; Link; Lipoprotein Receptor; Low Density Lipoprotein Receptor; Macroglobulins; Mediating; Membrane Microdomains; Metabolism; Morphology; N-terminal; Neuregulin Receptor; Neurites; Neuronal Differentiation; Neurons; Nuclear; Organ; Peptide Hydrolases; Phosphotyrosine; Process; Protein Isoforms; Protein Precursors; Proteins; Proteolysis; RNA Splicing; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Site; Testing; Variant; Work; amyloid precursor protein processing; cell type; extracellular; genetic association; in vivo; member; neurogenesis; neuropathology; notch protein; presenilin; programs; receptor; synaptogenesis; therapeutic target; transcription factor

Low density lipoprotein-receptor like protein 1 (LRP) is a transmembrane protein that has been directly and indirectly implicated in Alzheimer's disease (AD). LRP binds the longer splice variants of the Alzheimer amyloid protein precursor (APP) (APP751 and APP770), which contain a Kunitz protease inhibitory (KPI) domain. LRP also binds apolipoprotein E (Apo E), and a2-macroglobulin (A2M). APP, Apo E and A2M have all been genetically and biochemically implicated in AD. Polymorphism in LRP may also be associated with AD, although with weak effect. The cytoplasmic domain of LRP binds the adaptor FE65, a protein that also binds APP and may also show weak genetic association with AD. Finally, recent evidence indicates that, like APP, LRP undergoes a presenilin mediated intramembranous cleavage in a process now known as regulated intramembranous proteolysis (RIP). Presenilin is genetically and biochemically linked to AD and is directly involved in the formation of Abeta. In spite of the genetic and biochemical evidence for a role for LRP in AD-related proteins and processes, several questions remain unanswered. First, it is not clear whether the interactions between APP, Apo E or A2M and LRP stimulate a signal-transduction cascade through RIP that may affect cell function. Second, the degree to which LRP-interacting proteins can modulate APP processing and function is not fully understood. Finally, it remains obscure as to whether modulating such interactions may represent a therapeutic target in AD. In this Project, we will examine these questions, primarily focusing on dissecting the functional significance of the interactions between LRP and APP, Apo E, A2M, and FE65. Understanding the functional significance of these interactions will allow us to better understand the biochemical (and perhaps genetic) role of LRP in AD. Furthermore, such studies may contribute to our understanding of the biochemical (and perhaps genetic) role of the LRP interactors in AD. Finally, such studies may identify therapeutic targets in AD. We will also work with other Projects to elucidate the role of LRP in Abeta clearance and in statin effects. The central hypotheses of the current project are that LRP modulates APP metabolism, Abeta formation and clearance, and cell function contributing to Alzheimer's disease, and that LRP ligands mediate these effects. The specific aims of this proposal are: To characterize the effects of ligands of LRP on LRP localization and processing; To elucidate the effects of LRP on APP localization and processing, as well as Abeta formation; To dissect the cytoplasmic/nuclear complex of LRP that is involved in signaling and in modulating APP processing.; To identify genes that are regulated by the cytoplasmic/nuclear complex of LRP; To examine the function of LRP in neuronal differentiation in vivo; and, To define the role of LRP in the clearance and catabolism of Abeta in vivo.

低密度脂蛋白受体（如蛋白1（LRP））是一种跨膜蛋白，直接和间接与阿尔茨海默氏病有关（AD）。 LRP结合了阿尔茨海默氏淀粉样蛋白蛋白前体（APP）（APP751和APP770）的较长的剪接变体，该变体包含Kunitz蛋白酶抑制（KPI）域。 LRP还结合载脂蛋白E（APO E）和A2-杆球蛋白（A2M）。 App，Apo e和A2M都在遗传和生化上都与AD有关。 LRP中的多态性也可能与AD相关，尽管影响较弱。 LRP的细胞质结构域结合了适配器Fe65，该蛋白也结合了应用程序，并且也可能显示出与AD的遗传较弱的关联。最后，最近的证据表明，像APP一样，LRP在现在称为调节的膜内蛋白水解（RIP）的过程中经历了介导的膜内裂解。 Presenilin在遗传和生化上与AD相关，并直接参与ABETA的形成。尽管LRP在与AD相关的蛋白质和过程中的作用有遗传和生化证据，但几个问题仍未得到解决。首先，尚不清楚应用程序，APO E还是A2M和LRP之间的相互作用是否通过可能影响细胞功能的RIP刺激信号转导级联。其次，尚不完全了解LRP相互作用蛋白可以调节应用程序处理和功能的程度。最后，对于调节这种相互作用是否代表AD中的治疗靶标仍然晦涩难懂。在这个项目中，我们将主要研究这些问题 专注于解剖LRP和APP，APO E，A2M和FE65之间相互作用的功能意义。了解这些相互作用的功能意义将使我们能够更好地理解LRP在AD中的生化（也许是遗传）的作用。此外，此类研究可能有助于我们理解LRP相互作用者在AD中的生化作用（也许是遗传）的作用。最后，此类研究可以鉴定AD中的治疗靶标。我们还将与其他项目合作，阐明LRP在Abeta清除和他汀类药物效应中的作用。 当前项目的中心假设是，LRP调节应用代谢，ABETA形成和清除率以及有助于阿尔茨海默氏病的细胞功能，而LRP配体介导了这些作用。该提案的具体目的是：表征LRP配体对LRP定位和加工的影响；阐明LRP对应用程序本地化和处理以及Abeta形成的影响；剖析与信号传导和调节应用程序处理有关的LRP的细胞质/核复合物。识别 由LRP的细胞质/核复合物调节的基因；检查LRP在体内神经元分化中的功能；并且，定义了LRP在体内Abeta的清除和分解代谢中的作用。