SRF/MYOCD: new targets in Alzheimer's neurovasculature

描述（由申请人提供）：阿尔茨海默病（AD）是一种多因素神经退行性疾病。根据流行的淀粉样蛋白级联假说，AD的认知能力下降和明显的致病特征与淀粉样蛋白β肽（A?）在大脑中的异常积累有关。我们正在努力加强A？清除，防止其形成，还是发展抗A？小分子，最近的证据暗示神经血管功能障碍和脑血流量受损（CBF）在AD的发病机制。基于已发表的I期申请数据和本文提供的新颖初步数据，我们寻求从药理学上破坏来自AD患者的脑血管平滑肌细胞（VSMC）中两种转录因子，血清反应因子（SRF）和心肌素（心肌素）的活性增强。SRF/心肌构成了VSMC收缩基因程序的有效转录开关，该程序在AD-VSMC中被夸大，并且与导致AD小鼠模型中CBF减少的过度收缩表型相吻合。此外，新的初步数据支持SRF/心肌缺陷A？VSMC的清除和LRP1的表达，LRP1是a ？通过循环消除。综上所述，这些数据使我们提出以下假设：AD VSMC中SRF/心肌活性升高导致脑小动脉过度收缩表型和a ？导致脑血流减少和神经血管解耦，如A？然而，特异性阻断心肌与SRF相互作用的药物将“解锁”过度收缩的/ A？AD VSMC表型，改善脑血流，减轻痴呆症状。旨在验证这一假设的具体目标包括：(1)验证我们通过文库筛选确定的新型SRF/心肌小分子抑制剂；(2)评价先导化合物对VSMC超收缩性和A？体外清除率；(3)评估先导化合物对VSMC超收缩性的正常化能力。我们最近开发的一种新的阿尔茨海默病表型小鼠模型的清除和行为缺陷。这些创新和高度稳健的研究有望揭示一类新的潜在的阿尔茨海默病治疗药物，这些药物应该为进一步的毒性和临床前试验做好准备，从而为它们在阿尔茨海默病和痴呆相关的脑血管失调和神经血管解耦正常化方面的评估提供动力。目前，还没有有效的治疗方法来预防或逆转阿尔茨海默病（AD）和相关痴呆的不可阻挡的进程。这些神经退行性疾病的一个共同点是流向大脑的血液受到损害。本申请旨在评估一种潜在的新型治疗方法，旨在破坏阿尔茨海默病患者大脑血管中显示的两种过度活跃的蛋白质。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a multi-factorial neurodegenerative disorder. According to the prevailing amyloid cascade hypothesis, cognitive decline and distinct pathogenic features in AD relate to abnormal accumulation of amyloid beta-peptide (A?) in the brain. While efforts are underway to enhance A? clearance, prevent its formation, or to develop anti- A? small molecules, recent evidence implicates neurovascular dysfunction and compromised cerebral blood flow (CBF) in the pathogenesis of AD. Based on published data derived from our Phase I application and novel preliminary data provided herein, we seek to pharmacologically undermine enhanced activity of two transcription factors, serum response factor (SRF) and myocardin (MYOCD), in cerebral vascular smooth muscle cells (VSMC) derived from patients with AD. SRF/MYOCD constitute a potent transcriptional switch for a VSMC contractile gene program, which is exaggerated in AD-VSMC and coincides with a hypercontractile phenotype leading to reduced CBF in mouse models of AD. Moreover, new preliminary data support SRF/MYOCD in defective A? clearance by VSMC and the expression of LRP1, which is a major mediator of A? elimination via the circulation. Together, these data lead us to formulate the following hypothesis: elevated SRF/MYOCD activity in AD VSMC leads to a hypercontractile phenotype in small cerebral arteries and the accumulation of A? which contribute to CBF reductions and neurovascular uncoupling as seen in A?, whereas drugs which specifically block MYOCD interaction with SRF will "unlock" the hypercontractile/ A? AD VSMC phenotype, improve CBF and alleviate symptoms of dementia. The specific aims designed to test this hypothesis include (1) validating novel small molecule inhibitors of SRF/MYOCD we have identified through library screening; (2) evaluating lead compounds for their ability to normalize VSMC hypercontractility and A? clearance in vitro; and (3) evaluating lead compounds for their ability to normalize VSMC hypercontractility, A? clearance, and behavioral deficits in a novel mouse model of AD phenotype we have recently developed. These innovative and highly robust studies are expected to uncover a new class of potential AD therapeutics that should be poised well for further toxicity and preclinical trials, thus providing impetus for their assessment in normalizing the cerebrovascular dysregulation and neurovascular uncoupling associated with AD and dementia. Currently, there are no effective therapies to prevent or reverse the inexorable course of Alzheimer's disease (AD) and associated dementias. A common thread amongst such neurodegenerative diseases is a compromise in blood flow to the brain. This application seeks to evaluate a potential new class of therapeutics designed to disrupt two proteins shown to be hyperactive in blood vessels of the brain of AD patients.