Neurobiological Role of MicroRNA in Alzheimer's

 描述(申请人提供)：阿尔茨海默病(AD)是导致老年人痴呆症的最常见原因。由于目前的治疗方法提供了适度的症状缓解，并且不能减缓AD的进展，因此需要更好地了解AD病理的分子基础。这项提议将确定和验证microRNAs(MiRNAs)作为一类新的药物靶标。MiRNAs是一种内源性的、短的、非编码的RNA，通常通过与目标转录本的特定识别元件相互作用来抑制蛋白质的表达。AD被认为是由A？前体蛋白(APP)衍生的淀粉样多肽(A？)的过度产生所致，而参与A？合成的蛋白质(如APP、？？分泌酶/BACE1)的失调导致了A？的过度沉积。我们最近还发现，miRNA可以在与铁稳态相互作用中刺激APP的表达。我们建议研究miRNA对APP和BACE1的调控。我们假设特定的miRNAs调节内源性APP和BACE1的水平，在AD中是功能失调的，并且操作将降低A？特异性目标1(SA1)将确定APP和BACE1中具有功能的miRNA靶点，并验证miRNA对本地APP和BACE1表达的转录后调控。原理：使用发现APP和BACE1转录本的UTRs中的功能miRNA靶点。终点是APP和BACE1信使核糖核酸和蛋白，以及我们预测会随着miRNA变化的A？多肽。影响：操纵miRNA调节是一种新的治疗方法，可能对纠正AD的基因失调是可行的。SA2将测试SA1中验证的miRNA与其通过APP和BACE1表达的调控网络之间的生理相互作用。基本原理：测试其他可能与维持APP、BACE1和A？的动态平衡有关的调节机制。确定miRNA在该网络中的作用对于药理学靶向miRNA-转录本相互作用至关重要。影响：揭示阿尔茨海默病中miRNA功能的新机制。SA3将评估在AD动物模型中对有效的miRNA进行体内操作的效果。基本原理：在AD转基因动物中测试我们验证的miRNAs作为治疗靶点，包括通过诱导翻译中依赖miRNA的变化来与铁稳态相互作用。影响：在体内验证特定的miRNAs作为药物靶点，并确定与AD相关的新的调控网络。SA4将检查在AD患者中是否存在调节调控涉及A？稳态的基因产物的miRNAs。基本原理：在SA1-3中，我们将识别相关的miRNAs，这些miRNAs调节与Aü生产有关的基因产物的表达。如果这些miRNAs也参与AD病理，我们预计它们的调节将在解剖和病理依赖的模式中发生变化。影响：进一步证明miRNAs作为治疗靶点治疗AD相关调节障碍的有效性。由我们的中心假设指导的研究可能会通过阐明新的调控机制和识别调控AD相关重要基因产物的特定miRNAs而导致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来减缓或阻止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.