GALANIN REMOLDELING IN THE PROGRESSION OF AD

AD 进展过程中的甘丙肽重塑

• 批准号: 6927754
• 负责人: ELLIOTT Jay MUFSON
• 金额: $ 38.27万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927754
• 关键词: Alzheimer' s disease; RNA biosynthesis; cell differentiation; confocal scanning microscopy; galanin; gene induction /repression; human tissue; in situ hybridization; messenger RNA; nervous system regeneration; neural degeneration; neurogenesis; neurons; neuropeptide receptor; neuroprotectants; pathologic process; phosphorylation; prosencephalon; single cell analysis; synaptogenesis; tissue /cell culture

DESCRIPTION (provided by applicant): A crucial challenge in dementia research today is to understand the neurobiologic mechanisms underlying the degenerative and regenerative events which occur during the progression of Alzheimer's disease (AD). This PPG component will examine a set of hypotheses aimed at gaining greater insight into the galaninergic neural remodeling response associated with the survival of cholinergic basal forebrain (CBF) neurons in AD. Recent findings have led us to hypothesize that increased GAL may be neuroprotective for select CBF neurons since neural degeneration is least in the anterior CBF where GAL remodeling occurs, the loss of CBF neurons is minimal in people with mild cognitive impairment (MCI) and mild AD (50) at a point in the disease process where GAL remodeling begins (see Preliminary data), there is a 35% reduction in CBF neurons in the anterior CBF in mice lacking the GAL gene, GAL enhances neurite outgrowth in cultured sensory neurons and GAL and GAL receptors are expressed in embryonic stem cells suggesting a role in cell differentiation. The present application tests a series of hypotheses that during the transition from MCI to AD that 1) GAL remodeling enhances the expression of genes associated with neuroprotection, in anterior CBF neurons including nerve growth factor and its receptors and specific GAL receptor genes; 2) Selectively stabilizes the expression of genes associated with micortublular formation in CBF neurons containing site-specific tau phosphorylation epitopes using antibodies against site-specific tau phosphopeptides provided by Dr. Binder (Project 4); 3) GAL remodeling is associated with an increase in the number of GAL mRNA expressing neurons as AD progresses or alternatively there is an increase in GAL mRNA synthesis per anterior CBF neuron during disease progression, 4; There is an increase in GAL synaptic-like appositions upon anterior CBF hyper innervated neurons using a confocal microscope. GAL remodeling will be evaluated in individuals derived from the Rush Religious Orders Study with a clinical diagnosis of no cognitive impairment, MCI, and AD. The molecular findings will be correlated with cognitive (i.e., declarative, working and episodic memory), attention tests, pathology (i.e., Braak and Reagan Criteria, plaque load) and diagnostic categories. These investigations will lead to novel pharmacological treatments aimed at slowing the relentless onslaught of AD. Summary of the Project 3 Discussion: The revised application is seen as an improvement. There is a consensus that the reviewers recognized the work of Project 3 remains correlative, since no mechanistic investigations are planned; indeed, they may not even be possible when limiting the plan to study of human patient material. Aim 1 was viewed as the most interesting aspect of Project 3. For Aim 2, reviewers strongly urged the PL to include the development of probes to the three galanin receptors for use in the in situ hybridization studies. The sequences are known such that oligonucleotide probes can be as easily prepared as the plan for development of probes for galanin mRNA. A good deal of valuable information could be derived from their use.

描述（由申请人提供）：当今痴呆症研究中的一个关键挑战是 了解在阿尔茨海默氏病（AD）进展过程中发生的退化和再生事件的神经生物学机制。该PPG成分将研究一组旨在获得与AD中胆碱能基础前脑（CBF）神经元存活相关的甘氨酸能神经重塑反应的假设。最近的发现使我们假设GAL增加可能对某些CBF神经元具有神经保护作用，因为在发生GAL重塑发生的前CBF中，神经变性最少，而发生的CBF神经元的丧失是最小的CBF神经元在其中的轻度认知障碍（MCI）和轻度AD（50）的疾病过程中的PRER REMODERS（请参阅GAL REMODERS）（50）（50）。在缺乏GAL基因的小鼠前CBF中CBF神经元的降低，GAL在培养的感觉神经元中增强了神经突生长，而GAL和GAL受体在胚胎干细胞中表达，表明在细胞分化中起作用。本应用程序检验了一系列假设，这些假设在从MCI到AD的过渡期间1）GAL重塑增强了与神经保护相关的基因的表达， 在前CBF神经元中，包括神经生长因子及其受体和特定的GAL受体基因； 2）选择性地稳定与含有位点特异性tau磷酸化表位的CBF神经元中与MicorTublular形成相关的基因表达，并使用针对Binder博士提供的位点特异性TAU磷酸肽的抗体（项目4）； 3）GAL重塑与表达神经元的GAL mRNA数量的增加有关，或者在疾病进展过程中每个前CBF神经元的GAL mRNA合成增加，4；使用共聚焦显微镜，在前CBF过度神经神经元上，GAL突触样植入率有所增加。 GAL的重塑将在来自Rush宗教秩序研究的个体中进行评估，该研究的临床诊断没有认知障碍，MCI和AD。分子发现将是 与认知（即声明性，工作和情节记忆），注意测试，病理学（即Braak和Reagan标准，斑块负载）和诊断类别相关。这些调查将导致新型的药理学治疗，旨在减缓AD的不懈攻击。项目摘要3讨论：修订后的应用被视为改进。有一个共识，审稿人认识到项目3的工作仍然相关，因为没有计划进行机械调查；确实，在限制研究人类患者材料的计划时，它们甚至可能是不可能的。 AIM 1被视为项目3的最有趣的方面。对于AIM 2，审稿人强烈敦促PL将探针开发到三种Galanin受体中，以用于原位杂交研究。这些序列已知，因此寡核苷酸探针可以像开发加拉宁mRNA的探针的计划一样容易制备。可以从它们的使用中得出大量有价值的信息。