HUCBC modulation of Alzheimer-like pathology and behavioral changes

HUCBC 调节阿尔茨海默样病理和行为变化

• 批准号: 7391934
• 负责人: Jun Tan
• 金额: $ 14.04万
• 依托单位: SANERON CCEL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391934
• 关键词: Address; Adult; Alzheimer' s Disease; Amyloid; Amyloid deposition; Amyotrophic Lateral Sclerosis; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Astrocytosis; Behavioral; Blood Cells; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebrum; Clinical; Cognition; Cognitive; Cognitive deficits; Collection; Condition; Disease; Dose; Down-Regulation; Equilibrium; Goals; Human; Immunity; Immunization; Immunocompetent; Immunomodulators; Infarction; Inflammatory; Infusion procedures; Injection of therapeutic agent; Knowledge; Life Extension; Macular degeneration; Measures; Mediating; Microglia; Mononuclear; Multiple Sclerosis; Mus; Names; Nerve Degeneration; Neuraxis; Neurons; Outcome; Parkinson Disease; Pathogenesis; Pathology; Peptides; Performance; Pharmaceutical Preparations; Pre-Clinical Model; Property; Public Health; Radial; Research; Research Design; Role; Senile Plaques; Signal Transduction; Stroke; Testing; Therapeutic; Therapeutic Effect; Time; Trademark; Transgenic Organisms; Transplantation; Umbilical Cord Blood; Upper arm; Water; Work; amyloid pathology; base; clinical efficacy; cognitive change; cytokine; day; knowledge base; mouse model; peptide A; pre-clinical; programs; response

DESCRIPTION (provided by applicant): Modulation of the inflammatory cascade by several diverse strategies including A immunization, non-steroidal anti-inflammatory drug (NSAID) administration, and manipulation of microglial activation states have all been shown to reduce Alzheimer disease (AD)-like pathology, and cognitive deficits in AD transgenic mouse models. Our recent study demonstrated amelioration of AD-like pathology in PSAPP (APPswe, PSEN1dE9) mice when multiply injected with low dose of Saneron's human umbilical cord blood cells mononuclear fraction (HUCBC, trademark name "U-CORD-CELLTM"), a well known immunomodulator. This was observed through marked reduction of A?/?-amyloid plaques and associated astrocytosis. In concert with this down-regulation of pro-inflammatory signaling, cultured microglia isolated from HUCBC-infused PSAPP mice demonstrated increased A? phagocytic activity, thus clearly demonstrating HUCBC's potential immunomodulatory property. Although a typical reduction in cerebral A? plaque burden has been associated with an improvement in cognition, regarded as the true sign of improvement in AD, our study did not address either the behavioral or the cognitive changes associated with HUCBC injections. Thus, in this proposal we would like to test if HUCBC infusion can promote a rescue of behavioral and cognitive deficits and correlate these changes with their pathological improvements in PSAPP mice. Furthermore, we also plan to infuse these mice with human adult mononuclear fractions to demonstrate specific need for HUCBC rather than the adult mononuclear cells in order to observe these immunomodulatory and therapeutic effects. Based on these combined lines of evidence and our recent study, we hypothesize that multiple low dose injections of U-CORD-CELL" into transgenic PSAPP mice will provide a rescue of behavioral deficits, which will be correlated with improvements in AD-like pathology. The goal of this proposal is to establish a strong, well-integrated research program based on recently established roles of Th1/Th2 immunity, HUCBC transplantation, and AD pathogenesis. This knowledge is used to rationalize U-CORD-CELL" as a potentially safe and effective immunomodulatory therapy for AD.Project Narrative - Relevance to public health. In summary, we hypothesize that multiple low dose injections of Saneron's human umbilical cord blood cells mononuclear fraction (HUCBC, trademark name U-CORD-CELL") into transgenic PSAPP mice will provide a rescue of behavioral deficits, which will be correlated with improvements in AD-like pathology. The goal of this proposal is to establish a strong, well-integrated research program based on recently established roles of Th1/Th2 immunity, HUCBC transplantation, and AD pathogenesis. This knowledge is used to rationalize U-CORD-CELL" as a potentially safe and effective immunomodulatory therapy for AD.

描述（由申请人提供）：通过几种不同的策略（包括A免疫、非甾体抗炎药（NSAID）给药和操纵小胶质细胞活化状态）调节炎症级联反应，均显示可减少阿尔茨海默病（AD）样病理学和AD转基因小鼠模型中的认知缺陷。我们最近的研究表明，当多次注射低剂量的Saneron人脐带血细胞单核组分（HUCBC，商标名“U-CORD-CELLTM”）（一种众所周知的免疫调节剂）时，PSAPP（APPswe，PSEN 1dE 9）小鼠的AD样病理学得到改善。这是通过A？/？-淀粉样斑块和相关的星形细胞增多症。与此一致的促炎信号的下调，培养的小胶质细胞从HUCBC输注PSAPP小鼠分离表现出增加A？吞噬活性，从而清楚地证明HUCBC的潜在免疫调节特性。虽然一个典型的减少大脑A？斑块负荷与认知的改善相关，被认为是AD改善的真正标志，我们的研究没有解决与HUCBC注射相关的行为或认知变化。因此，在本提案中，我们想测试HUCBC输注是否可以促进行为和认知缺陷的拯救，并将这些变化与PSAPP小鼠的病理学改善相关联。此外，我们还计划向这些小鼠输注人成体单核细胞组分，以证明对HUCBC而不是成体单核细胞的特异性需求，从而观察这些免疫调节和治疗效果。 基于这些综合证据和我们最近的研究，我们假设多次低剂量注射U-CORD-CELL到转基因PSAPP小鼠中将提供行为缺陷的拯救，这将与AD样病理学的改善相关。该提案的目标是建立一个强大的，良好的综合研究计划的基础上，最近建立的作用，Th 1/Th 2免疫，HUCBC移植，和AD发病机制。这一知识被用来合理化U-CORD-CELL”作为一种潜在的安全和有效的免疫调节治疗AD。项目叙述-与公共卫生的相关性。总之，我们假设将Saneron的人脐带血细胞单核部分（HUCBC，商标名U-CORD-CELL）多次低剂量注射到转基因PSAPP小鼠中将提供行为缺陷的拯救，这将与AD样病理学的改善相关。该提案的目标是建立一个强大的，良好的综合研究计划的基础上，最近建立的作用，Th 1/Th 2免疫，HUCBC移植，和AD发病机制。这一知识被用来合理化U-CORD-CELL”作为一种潜在的安全和有效的免疫调节治疗AD。