International Research Fellowship Program : Using Drosophila to Study the Biology of polyQ Neurodegeneration

国际研究奖学金计划：利用果蝇研究 PolyQ 神经变性的生物学

• 批准号: 0651049
• 负责人: Suzanne Ziegenhorn
• 金额: $ 10万
• 依托单位: Ziegenhorn Suzanne L
• 依托单位国家: 美国
• 项目类别: Fellowship Award
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0651049&HistoricalAwards=false
• 关键词: International; Research; Fellowship; Program; Using

0651049ZiegenhornThe International Research Fellowship Program enables U.S. scientists and engineers to conduct nine to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.This award will support a twenty-four-month research fellowship by Dr. Suzanne L. Ziegenhorn to work with Dr. Gaiti Hasan at the National Centre for Biological Sciences in Bangalore, India. Support for this project is provided by the Office of International Science and Engineering's Africa, Near East, and South Asia Program (ANESA).Calcium deregulation in GABAergic medium spiny striatal neurons (MSNs) has recently been implicated in the specific sensitivity of these cells to polyQ expanded Huntingtin (Htt exp) and may explain why these cells are targeted for degeneration in Huntington's Disease (HD). In mouse MSNs, it has been demonstrated that Httexp, but not Htt, sensitizes the inositol (1,4,5)-triphosphate receptor type 1 (InsP3R1) to InsP3, leading to increased Ca2+ release. If indeed calcium dysfunction contributes to HD progression, a family of new therapies, namely Ca2+ signaling inhibitors, may be of use in treating patients who suffer from this disorder.Drosophila is an excellent organism in which to examine the potential contribution of deranged Ca2+ homeostasis to neurodegenerative disease progression as there is a single InsP3R gene (itpr) in the genome. Due to the functional similarity of Drosophila InsP3R to the mouse receptor and the growing body of evidence that suggests that HD is a disorder characterized by Ca2+ homeostasis deregulation, investigating the role of itpr in regulating degeneration of Drosophila photoreceptor neurons induced by polyQ-expanded human Huntington may reveal insights into the disease state. The InsP3R channel function has been assessed for several viable heteroallelic itpr mutant combinations and the results have led to the grouping of these combinations into three classes, those that release more Ca2+ in response to InsP3, those that release less, and those that appear to respond similarly to wild-type. To assess the effect of various types of InsP3R-mediated Ca2+ dysfunction on neural degeneration, expression of the N-terminal polyQ domain-containing fragment of Htt with polyQ tracts of varying lengths is targeted to the photoreceptor neurons in the viable heteroallelic itpr mutants. The effects on photoreceptor degeneration are determined over a time course to show the progressive nature of Htt exp-induced degeneration. Further, to examine if the degeneration that results from Htt exp can be prevented, reversed, or enhanced by treatment with drugs that affect Ca2+, larvae that are expressing Htt exp are treated with drugs that either inhibit or promote Ca2+ signaling and the effect of these compounds on photoreceptor degeneration are assayed. Additionally, intracellular Ca2+ signals can be altered by genetic means by utilizing existing mutations in other known Ca2+ channels and sensors to determine their effects on tissue degeneration in flies expressing Htt exp. Compounds that reduce the severity or delay the onset of HD symptoms this system may serve as a potential therapy for HD, opening up the possibility that many additional compounds that act by modulating Ca2+ signaling may be of use in the treatment of this disorder.

Ziegenhorst国际研究奖学金计划使美国科学家和工程师能够在国外进行9到24个月的研究。 该计划的奖项提供了联合研究的机会，以及使用独特或互补的设施，专业知识和国外的实验条件。Ziegenhorn将与印度班加罗尔国家生物科学中心的Gaiti Hasan博士合作。 该项目由国际科学与工程办公室的非洲、近东和南亚项目（ANESA）提供支持。GABA能中型棘状纹状体神经元（MSN）中的钙失调最近与这些细胞对polyQ扩增的亨廷顿蛋白（Htt exp）的特异性敏感性有关，并可能解释为什么这些细胞是亨廷顿病（HD）变性的靶细胞。 在小鼠MSN中，已经证明Httexp而不是Htt使肌醇（1，4，5）-三磷酸受体1型（InsP 3R 1）对InsP 3敏感，导致Ca 2+释放增加。 如果确实钙功能障碍有助于HD进展，一个家庭的新疗法，即Ca 2+信号传导抑制剂，可能是用于治疗患有这种disorder.Drosophila的患者是一个很好的生物体，其中检查的潜在贡献错乱的Ca 2+稳态神经退行性疾病的进展，因为有一个单一的InsP 3R基因（itpr）的基因组中。由于果蝇InsP 3 R与小鼠受体的功能相似性以及越来越多的证据表明HD是一种以Ca 2+稳态失调为特征的疾病，因此研究itpr在调节由polyQ扩增的人亨廷顿诱导的果蝇感光神经元变性中的作用可能揭示对疾病状态的见解。 InsP 3R通道功能已被评估为几个可行的异等位基因itpr突变体组合，结果导致这些组合分为三类，那些释放更多的Ca 2+响应InsP 3，那些释放较少，和那些似乎响应类似于野生型。 为了评估各种类型的InsP 3R介导的Ca 2+功能障碍对神经变性的影响，将具有不同长度的polyQ束的Htt的N-末端含polyQ结构域的片段的表达靶向于可行的异等位基因itpr突变体中的感光神经元。 在一段时间内确定对感光细胞变性的影响，以显示Htt exp-induced变性的进行性。 此外，为了检查由Htt ex引起的变性是否可以通过影响Ca 2+的药物治疗来预防、逆转或增强，用抑制或促进Ca 2+信号传导的药物处理表达Htt ex的幼虫，并分析这些化合物对光感受器变性的影响。 此外，细胞内Ca 2+信号可以通过遗传手段改变，通过利用其他已知的Ca 2+通道和传感器中的现有突变来确定它们对表达Htt exp的果蝇中的组织变性的影响。 降低HD症状严重程度或延迟HD症状发作的化合物可以作为HD的潜在疗法，打开了许多通过调节Ca 2+信号传导起作用的其他化合物可以用于治疗这种疾病的可能性。