Pathogenesis of Chronic Wasting Disease in Transgenic Mice

转基因小鼠慢性消耗性疾病的发病机制

• 批准号: 8662829
• 负责人: Davis Martin Seelig
• 金额: $ 11.1万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662829
• 关键词: Address; Anatomy; Apoptosis; Applications Grants; Area; B-Lymphocytes; Biological Assay; Blood; Bone Marrow; Bone Marrow Cells; Brain; Cell Death; Cell Lineage; Cells; Cessation of life; Chronic Wasting Disease; Clinical; Collaborations; Communicable Diseases; Confocal Microscopy; Deer; Dendritic Cells; Development; Development Plans; Diagnostic; Disease; Doctor of Philosophy; Documentation; Domestic Animals; Drug or chemical Tissue Distribution; Elements; Employment; Equine mule; Evaluation; Event; Excretory function; Extramural Activities; Flow Cytometry; Genitourinary system; Genomics; Glial Fibrillary Acidic Protein; Gliosis; Goals; Hematogenous; Hematopoietic; Horizontal Disease Transmission; Human; ITGAM gene; Immunofluorescence Immunologic; Immunohistochemistry; In Situ; Infection; Institution; International; Intervention; Intravenous; Investigation; Journals; Kinetics; Knowledge; Label; Laboratories; Lesion; Manuscripts; Marrow; Mediating; Mediator of activation protein; Mentors; Microscopic; Modeling; Molecular Profiling; Monitor; Mus; Myelogenous; Necrosis; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Neurons; Neuropathogenesis; Oral; Pathogenesis; Pathologist; Pathology; Pathway interactions; Pattern; Peer Review; Performance; Peripheral; Peripheral Nerves; Pilot Projects; Population; PrP; Predisposition; Prion Diseases; Prion Pathway; Prions; Process; Publishing; Relative (related person); Research; Research Personnel; Research Training; Risk; Role; Route; Saliva; Salivary Glands; Sampling; Scanning; Simulate; Site; Study Section; Tail; Text; Therapeutic; Time; Tissues; Tongue; Transgenic Mice; Transgenic Organisms; Transplantation; Tropism; Urine; Western Blotting; Work; abstracting; base; career; career development; caspase-3; cell injury; cervid; design; disease transmission; immunocytochemistry; in vivo; insight; intraperitoneal; macrophage; meetings; monocyte; neuron apoptosis; neuron loss; neuropathology; novel; particle; programs; promoter; protein distribution; protein expression; protein transport; relating to nervous system; research study; response; spatial relationship; tissue tropism; trafficking

DESCRIPTION (provided by applicant): Abstract PI: SEELIG, DAVIS MARTIN Project: 1K01AI082173-01A2 Title: Pathogenesis of Chronic Wasting Disease in Transgenic Mice Accession Number: 3245923 ================== NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== This proposal employs a transgenic murine model of chronic wasting disease (CWD) to addresses sequential prion pathogenesis and the role of bone marrow in prion trafficking and neuroinvasion. The goals of the proposed studies are: (1) to characterize the multiple aspects of the pathogenesis of CWD in transgenic, cervid PrP-expressing (Tg[CerPrP]) mice by evaluation of sequential patterns of prion tissue tropism and neuropathology; and (2) to address the role of the bone marrow and its cellular progeny in the prion trafficking and pathogenesis through reciprocal transplantation studies. We will utilize a combination of single- and dual- labeling immunohistochemistry (IHC), western blotting (WB), and immunofluorescent confocal microscopy to detect accumulations of misfolded prion protein (PrPres) in conjunction with markers of neuropathology. To define the role of the bone marrow in prion trafficking and hematogenous neuroinvasion, we will use reciprocal adoptive bone marrow transfer to create two lineages of chimeric mice, which will have PrPc expression restricted to hematopoietic or non-hematopoietic compartments. We will characterize these mice through flow cytometry, and document sequential PrPres accumulation via IHC and WB. We expect that the CWD-infected mice will mimic naturally-infected cervids with respect to susceptibility, clinical disease, microscopic neuropathology, and PrPres distribution. We hypothesize/anticipate that CWD-infected mice will reveal novel, neuropathologic features of prion disease, including increased expression of markers of gliosis, neuronal loss and apoptosis adjacent to areas of PrPres accumulation. In the adoptive bone marrow transfer experiments, we hypothesize that marrow of CWD-infected Tg[CerPrP] mice will contain infectious prions, which will be associated with myeloid lineage cells. Additionally, we hypothesize that these cells will ferry PrPres to the brain as part of cell renewal and trafficking patterns. The results of these studies will enhance understanding of the mechanisms of prion disease-associated neuropathology, help inform anti-prion disease therapeutic strategies, and explore an under-investigated pathway of prion dissemination. Using the proposed experiments, my short- term objective will be to complete my PhD in the summer of 2010; my long term goal will then be to devote myself to a becoming a successful independent researcher. The key elements of the research career development plan designed to accomplish these goals include: (1) the establishment of an advisory/mentoring panel to help establish and monitor career performance milestones; (2) the identification and successful employment as an investigative pathologist in a research-focused department and institution with a well- established infectious disease and/or neurodegenerative program; (3) participation in extramural research training opportunities at established centers of prion and neurodegenerative disease; (4) submission of peer- reviewed manuscripts and extramural grant applications, and (5) extended responsibility and participation in laboratory, departmental, and national/international meetings and journal clubs. A critical limitation in the development of prion disease diagnostic and intervention strategies is the lack of knowledge regarding mechanisms of prion-disease neurodegeneration and in vivo prion trafficking. The work proposed in the application aims to address these limitations by evaluating the accumulation patterns of a marker of prion disease (PrPres) in proximity to specific markers of neuronal pathology which may implicate specific cell populations or pathways capable of being reversed or antagonized. Additionally, our studies will inform us regarding a novel site of PrPres accumulation (the bone marrow) and a novel pathway of prion trafficking (the blood), which will enhance the development of prion disease diagnostics and treatment.

描述（由申请人提供）： 摘要 PI：SEELIG，DAVIS MARTIN 项目：1 K 01 AI 082173 - 01 A2标题：转基因小鼠慢性消耗性疾病的发病机制登录号：3245923 ================== 注意事项：本摘要摘自应用程序，未经SRA验证。当应用程序扫描过程出现问题时，提取的文本可能不正确或不完整。 ================== 该建议采用慢性消耗性疾病（CWD）的转基因小鼠模型，以解决序列朊病毒的发病机制和骨髓中的朊病毒运输和神经侵袭的作用。拟定研究的目的是：（1）通过评价朊病毒组织嗜性和神经病理学的顺序模式，表征转基因、表达鹿PrP（Tg[CerPrP]）小鼠中CWD发病机制的多个方面;（2）通过相互移植研究，阐明骨髓及其细胞子代在朊病毒运输和发病机制中的作用。我们将利用单标记和双标记免疫组织化学（IHC）、蛋白质印迹（WB）和免疫荧光共聚焦显微镜的组合来检测错误折叠朊病毒蛋白（PrPres）与神经病理学标志物的积聚。为了确定骨髓在朊病毒运输和造血性神经侵袭中的作用，我们将使用相互过继骨髓转移来创建两个谱系的嵌合小鼠，其将具有限于造血或非造血区室的PrPc表达。我们将通过流式细胞术表征这些小鼠，并通过IHC和WB记录连续的PrPres积累。我们预计，CWD感染的小鼠将模仿自然感染的鹿科动物的易感性，临床疾病，显微神经病理学，和PrPres分布。我们假设/预期，CWD感染的小鼠将揭示朊病毒疾病的新的神经病理学特征，包括神经胶质增生标记物的表达增加，神经元丢失和邻近PrPres积聚区域的凋亡。在过继骨髓转移实验中，我们假设CWD感染的Tg[CerPrP]小鼠的骨髓将含有感染性朊病毒，其将与髓系细胞相关。此外，我们假设这些细胞将作为细胞更新和贩运模式的一部分将PrPres运送到大脑。这些研究的结果将增强对朊病毒疾病相关神经病理学机制的理解，有助于告知抗朊病毒疾病的治疗策略，并探索朊病毒传播的研究不足的途径。使用拟议的实验，我的短期目标将是在2010年夏天完成我的博士学位，我的长期目标将是致力于成为一个成功的独立研究人员。为实现这些目标而设计的研究职业发展计划的关键要素包括：（1）建立咨询/指导小组，以帮助建立和监测职业绩效里程碑;（2）在具有完善的传染病和/或神经退行性疾病项目的研究部门和机构中确定并成功雇用调查病理学家;（3）在已建立的朊病毒和神经退行性疾病中心参与校外研究培训机会;（4）提交同行评审的手稿和校外资助申请;（5）扩大责任和参与实验室、部门和国家/国际会议和期刊俱乐部。在朊病毒疾病诊断和干预策略的发展中的一个关键限制是缺乏关于朊病毒疾病神经变性和体内朊病毒运输机制的知识。该申请中提出的工作旨在通过评估朊病毒病标志物（PrPres）在神经元病理学的特定标志物附近的积累模式来解决这些限制，所述神经元病理学的特定标志物可能涉及能够被逆转或拮抗的特定细胞群或途径。此外，我们的研究将告知我们关于PrPres积累的新位点（骨髓）和朊病毒运输的新途径（血液），这将促进朊病毒疾病诊断和治疗的发展。

项目成果

Calibrated Bioresorbable Microspheres as an Embolic Agent: An Experimental Study in a Rabbit Renal Model.

• DOI: 10.1016/j.jvir.2015.01.014
• 发表时间: 2015-12
• 期刊: Journal of vascular and interventional radiology : JVIR
• 作者: Weng L;Seelig D;Rostamzadeh P;Golzarian J
• 通讯作者: Golzarian J

Pathology in practice. Renal adenocarcinoma (solid and tubular, clear cell type) with intravascular invasion and paraneoplastic leukocytosis in a dog.

病理学实践。

• DOI: 10.2460/javma.246.9.973
• 发表时间: 2015
• 期刊: Journal of the American Veterinary Medical Association
• 作者: Benson,CatherineJ;Stiller,AmberT;Corbin,ErinE;Schucker,Adrienne;Seelig,DavisM
• 通讯作者: Seelig,DavisM

The Comparative Diagnostic Features of Canine and Human Lymphoma.

• DOI: 10.3390/vetsci3020011
• 发表时间: 2016-06-01
• 期刊: Veterinary sciences
• 影响因子: 2.4
• 作者: Seelig, Davis M;Avery, Anne C;Linden, Michael A
• 通讯作者: Linden, Michael A