Elucidating the cellular mechanisms of prion propagation and clearance for devisi

阐明朊病毒传播和清除的细胞机制

• 批准号: 8847411
• 负责人: Donald L. Jarvis
• 金额: $ 30.95万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847411
• 关键词: Address; Aging; Animals; Autophagocytosis; Biological; Biology; Cells; Communicable Diseases; Data; Development; Devices; Disease; Epidemic; Equilibrium; Event; Functional disorder; Genetic; Goals; Health; In Vitro; Incidence; Infection; Intervention; Modeling; Molecular; Molecular and Cellular Biology; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Pathway interactions; Physiological; Physiology; PrP; PrPSc Proteins; Prion Diseases; Prions; Protein Isoforms; Proteins; Quality Control; Recycling; Research; Seeds; Societies; Sorting - Cell Movement; Therapeutic; Work; cellular targeting; fight against; in vivo; insight; man; novel; prion-like; programs; prophylactic; protein expression; protein misfolding; research study; transmission process

DESCRIPTION (provided by applicant): Elucidating the cellular mechanisms of prion propagation and clearance for devising new targets for intervention in prion disease There are an increasing number of neurodegenerative disorders which result from the aggregation of misfolded proteins and which share patho-physiological mechanisms. Prion diseases are the prototypical protein misfolding diseases, and their pathogenesis is associated solely with aberrant misfolding of a single cellular protein (PrPc). Prion diseases are unique in this group as they are infectious disorders found in man and animals. Besides sporadic or genetic manifestation, they can be acquired by infection and transmitted between species, resulting in endemic or epidemic scenarios (e.g. BSE/vCJD and CWD). They can be controlled, but eradication is impossible. Therefore, it is mandatory to understand the molecular and cellular requirements for propagation and transmission of prions in order to device rational strategies for controlling these events. Advances in understanding prion patho-physiology will have major implications for other protein misfolding diseases, as it may help elucidate common cellular mechanisms. Such understanding is of fundamental scientific importance as neurodegenerative diseases represent one of the biggest health problems in our aging society, and uncovering molecular mechanisms of general validity is fundamental for the identification of new targets and development of rational therapies. The long-term goal of our group is to develop therapeutic and prophylactic anti-prion strategies. The overall objective we have is to study the cellular and molecular biology of prion infections and to use gained understanding for delineating novel targets for intervention. We have focused our attempts on two main strategies. One is the endogenous cellular clearance capacity for prions, the other one is to target the cellular isoform PrPc, which is a prerequisite for prion conversion and execution of neurodegeneration. It is our central hypothesis that it is feasible to interfere in prion propagation by increasing the cellular clearance for prions. Work in Aim 1 will substantiate our finding that prion clearance can be enhanced by compound-induced induction of autophagy, a basic cellular program for degradation and recycling. The proposed work intends to better understand the underlying molecular mechanisms and to validate the therapeutic and translational potential of this finding in vivo. Work in Aim 2 and 3 addresses cellular modifiers of prion formation. We have found that a basal level of autophagy is needed for establishing prion infection and we propose that autophagy represents the biological equivalent for the postulated disaggregase function in mammalian prion/prion-like biology. Our goal is to prove this at the cellular and molecular level. The rational for work in Aim 3 is that protein quality control mechanisms in the secretory pathway can directly influence prion conversion by determining on the quality of conversion substrates. We want to manipulate this by over-expressing folding and sorting proteins, in order to show that this represents a novel pathway counteracting prion propagation. Overall, our studies will provide mechanistic insights into basic cellular and molecular mechanisms which are relevant for neurodegenerative diseases and will result in novel targets for rational therapy against prion diseases and protein misfolding disorders.

描述（由申请人提供）：阐明朊病毒增殖和清除的细胞机制，用于设计新的朊病毒疾病干预靶点。越来越多的神经退行性疾病是由错误折叠的蛋白质聚集引起的，并且具有共同的病理生理机制。朊病毒病是典型的蛋白质错误折叠疾病，其发病机制仅与单个细胞蛋白（PrPc）的异常错误折叠有关。朊病毒疾病在这一群体中是独特的， 它们是在人和动物中发现的传染性疾病。除了散发或遗传表现外，它们还可通过感染获得并在物种之间传播，导致地方性或流行性情况（例如BSE/vCJD和CWD）。它们可以被控制，但根除是不可能的。因此，必须了解朊病毒的繁殖和传播的分子和细胞要求，以便设计控制这些事件的合理策略。了解朊病毒病理生理学的进展将对其他蛋白质错误折叠疾病产生重大影响，因为它可能有助于阐明常见的细胞机制。这种理解具有根本的科学重要性，因为神经退行性疾病代表了我们老龄化社会中最大的健康问题之一，并且揭示一般有效性的分子机制对于识别新靶点和开发合理疗法至关重要。我们小组的长期目标是开发治疗性和预防性的抗朊病毒策略。我们的总体目标是研究朊病毒感染的细胞和分子生物学，并利用所获得的理解来描绘新的干预目标。我们的努力集中在两个主要战略上。一个是内源性细胞对朊病毒的清除能力，另一个是靶向细胞亚型PrPc，这是朊病毒转化和执行神经变性的先决条件。我们的中心假设是，通过增加细胞内的蛋白质含量来干扰朊病毒的传播是可行的。 清除朊病毒目标1中的工作将证实我们的发现，即朊病毒清除可以通过化合物诱导的自噬（降解和回收的基本细胞程序）来增强。拟议的工作旨在更好地了解潜在的分子机制，并验证这一发现在体内的治疗和转化潜力。目标2和3中的工作涉及朊病毒形成的细胞修饰剂。我们已经发现，自噬的基础水平是建立朊病毒感染所必需的，我们提出，自噬代表了哺乳动物朊病毒/朊病毒样生物学中假定的解聚酶功能的生物等效物。我们的目标是在细胞和分子水平上证明这一点。目标3中工作的理由是分泌途径中的蛋白质质量控制机制可以通过确定转化底物的质量来直接影响朊病毒转化。我们希望通过过度表达折叠和分选蛋白来操纵它，以表明这代表了一种新的抵抗朊病毒传播的途径。总体而言，我们的研究将为与神经退行性疾病相关的基本细胞和分子机制提供机理见解，并将为针对朊病毒疾病和蛋白质错误折叠疾病的合理治疗提供新的靶点。