The role of ciliary melanin-concentrating hormone receptors in Alzheimer's disease

项目摘要 初生纤毛是具有感官功能的细胞器。纤毛病被定义为一种与 纤毛功能或结构不正常。纤毛疾病与肾脏、肝脏和 心血管疾病。然而，阿尔茨海默病(AD)是否为 与纤毛功能和结构有关。在这份行政补充提案中，我们结合了专业知识 来自邻近机构的两个实验室。这项多PI提案包括Surya Nauli博士(查普曼 其实验室在询问初级纤毛功能方面有很好的记录，以及Amal Alachkar博士 (加州大学欧文分校)，其研究小组在神经性退行性变方面拥有丰富的专业知识 广告。这项建议的总体目标是研究早期和早期纤毛结构和功能的变化。 阿尔茨海默病晚期小鼠大脑。已知黑色素浓缩激素受体(MCHR1)定位于 额叶皮质和海马区内神经细胞的纤毛。在目标1中，我们将调查删除 表达MCHR1的纤毛加剧了5xFAD小鼠模型的认知障碍。我们将同时使用纤毛和 AD小鼠模型，研究这些小鼠的行为和记忆变化。在目标2中，我们检查是否有选择性 睫状肌MCHR1的药理学靶向改善AD的认知功能障碍。我们将应用纳米颗粒- 靶向，这是父母赠款的一部分，用于评估睫状MCHR1靶向治疗是否改善了 5xFAD-AD小鼠的行为缺陷。这些有限研究的结果提供了新的知识，如果MCHR1- 纤毛(Aim 1)和纤毛MCHR1(Aim 2)的表达与AD小鼠的行为缺陷有关。

Project Abstract Primary cilia are cellular organelles with sensory functions. Ciliopathy is defined as a disease associated with abnormal cilia function or structure. Ciliopathies are associated with expanding spectrum of kidney, liver, and cardiovascular disorders. However, it is yet to be investigated whether or not Alzheimer’s disease (AD) is associated with cilia function and structure. In this Administrative Supplement proposal, we combine expertise from two laboratories of the neighboring institutions. This multi-PI proposal includes Dr. Surya Nauli (Chapman University), whose laboratory has strong records in interrogating primary cilia functions, and Dr. Amal Alachkar (the University of California, Irvine), whose research group has strong expertise in neurological degeneration of AD. The overall goal of this proposal is to examine the alterations of cilia structure and functions in early- and late-stage AD mouse brains. It is known that melanin concentrating hormone receptor (MCHR1) is localized in cilia of neuronal cells within the frontal cortex and hippocampus. In Aim 1, we will investigate if the deletion of MCHR1-expressing cilia exacerbates cognitive deficits in 5xFAD mouse model of AD. We will use both cilia and AD mouse models to study behavioral and memory changes in these mice. In Aim 2, we examine if selective pharmacological targeting of ciliary MCHR1 improve cognitive deficits in AD. We will apply nanoparticle- targeting, which is part of the parental grant to evaluate if ciliary MCHR1-targeted therapy improves the behavioral deficits in 5xFAD-AD mice. The outcomes of these limited studies offer new knowledge if MCHR1- expressed cilia (Aim 1) and ciliary MCHR1 (Aim 2) are involved in behavioral deficits in AD mice.