Neurobiological Role of MicroRNA in Alzheimer's

 描述（由申请人提供）：阿尔茨海默病（AD）是老年痴呆症的最常见原因。由于目前的治疗提供了适度的症状缓解，并没有减缓AD的进展，更好地了解AD病理的分子基础是必要的。该提案将鉴定和验证microRNAs（miRNAs）作为一类新的药物靶点。miRNA是内源性的、短的、非编码RNA，其通常通过与靶转录物的特异性识别元件相互作用来抑制蛋白质表达。AD被认为是由淀粉样蛋白-β-肽（A β）的过度产生引起的，所述A β-肽衍生自A β-前体蛋白（APP），并且参与A β-肽产生的蛋白质（例如APP、β-分泌酶/BACE 1）的失调有助于A β-肽的过度沉积。我们最近还发现，miRNA可以刺激APP表达与铁稳态的相互作用。我们计划研究APP和BACE 1通过miRNA的调节。我们假设特定的miRNAs调节APP和BACE 1的内源性水平，在AD中功能失调，并且操纵将减少Ablation。特异性目标1（SA 1）将鉴定APP和BACE 1中的功能性miRNA靶位点，并验证天然APP和BACE 1表达的miRNA转录后调控。基本原理：使用发现APP和BACE 1转录物UTR中的功能性miRNA靶点。终点是APP和BACE 1 mRNA和蛋白质，以及我们预测会随miRNA变化的AAPs肽。影响：操纵miRNA调控是一种新的治疗方法，可能适用于纠正AD中的基因失调。SA 2将测试在SA 1中验证的miRNA与它们在APP和BACE 1表达上的调控网络之间的生理相互作用。基本原理：检测可能与维持APP、BACE 1和ApoA稳态相关的其他调节机制。确定miRNA在该网络中的作用对于确定靶向miRNA-转录本相互作用至关重要。影响：揭示AD中miRNA功能的新机制。SA 3将评估经验证的miRNA在AD动物模型中的体内操作的效果。基本原理：在AD转基因动物中测试我们验证的miRNA作为治疗靶点，包括通过诱导miRNA依赖性翻译变化与铁稳态的相互作用。影响：作为体内药物靶点的AD特异性miRNA，并确定新的AD相关调控网络。SA 4将检查参与调节控制基因产物的miRNA是否在AD患者中失调，所述基因产物参与AD稳态。基本原理：在SA 1 -3中，我们将鉴定出调节与Ablast产生有关的基因产物表达的相关miRNA。如果这些miRNAs也参与AD病理学，我们预计它们的调节在解剖学和病理学依赖性模式中会有所不同。影响：进一步证明miRNA作为治疗AD相关失调的治疗靶点的有效性。由我们的中心假设所决定的研究可能会通过阐明新的调控机制和鉴定调节AD中涉及的重要基因产物的特定miRNA来引起该领域的重大范式转变。最终的影响将是最终使用这些新的药物靶点来生产治疗药物，以减缓或阻止AD的进展。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Because current treatments provide modest symptomatic relief and do not slow AD progression, a better understanding of molecular bases of AD pathology is needed. This proposal will identify and validate microRNAs (miRNAs) as a new class of drug targets. miRNAs are endogenous, short, non-coding RNAs that typically inhibit protein expression by interacting with specific recognition elements of target transcripts. AD is believed to result from overproduction of amyloid-ß peptide (Aß), derived from Aß precursor protein (APP), and dysregulation of proteins involved in Aß production (e.g. APP, ß-secretase/BACE1) contributes to excess Aß deposition. We have also recently found that miRNA can stimulate APP expression in interaction with iron homeostasis. We propose to study APP and BACE1 regulation by miRNA. We hypothesize specific miRNAs regulate endogenous levels of APP and BACE1, are dysfunctional in AD, and manipulation will reduce Aß. Specific Aim 1(SA1) will identify functional miRNA target sites in APP and BACE1 and validate miRNA post-transcriptional regulation of native APP and BACE1 expression. Rationale: Discover functional miRNA targets in UTRs of APP and BACE1 transcripts using. Endpoints are APP and BACE1 mRNA & proteins, and Aß peptides, which we predict to change with miRNA. Impact: Manipulation of miRNA regulation is a novel therapeutic approach and may be feasible for correcting gene dysregulation in AD. SA2 will test physiological interactions between miRNA validated in SA1 and their regulatory networks over APP and BACE1 expression. Rationale: Test other mechanisms of regulation likely linked to maintain homeostasis of APP, BACE1 and Aß. Identifying roles of miRNA in this network is vital to pharmacologically target miRNA-transcript interactions. Impact: Reveal novel mechanisms for miRNA function in AD. SA3 will assess effects of in vivo manipulation of validated miRNA in AD animal models. Rationale: Test our validated miRNAs as therapeutic targets in AD transgenic animals, including interaction with iron homeostasis, by inducing miRNA-dependent changes in translation. Impact: Validate specific miRNAs as drug targets in vivo and identify novel AD-related regulatory networks. SA4 will examine whether miRNAs implicated in regulatory control of gene products involved in Aß homeostasis are dysregulated in AD patients. Rationale: In SA1-3, we will identify pertinent miRNAs that modulate expression of gene products implicated in Aß production. If these miRNAs are also involved in AD pathology, we expect their regulation to vary in anatomical- and pathology-dependent patterns. Impact: Further demonstrate validity of miRNAs as therapeutic targets to treat AD-related dysregulation. Research dictated by our central hypothesis could cause a significant paradigm shift on the field by elucidating novel regulatory mechanisms and identifying specific miRNAs that regulate important gene products implicated in AD. Final impact will be in eventual use of these new drug targets to produce therapeutic agents to slow or halt progression in AD.