RESCUING MOTOR DEFICITS IN SHANK3 RELEATED DISORDERS

挽救 3 号小腿相关疾病中的运动缺陷

• 批准号: 9767290
• 负责人: JIMMY L HOLDER
• 金额: $ 18.42万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767290
• 关键词: Actins; Adenylate Cyclase; Advisory Committees; Area; Automobile Driving; Bacterial Artificial Chromosomes; Behavior; Behavioral; Biochemistry; Bioinformatics; Clinical; Corpus striatum structure; Coupled; Cytoskeleton; Data; Development Plans; Disease; Doctor of Medicine; Doctor of Philosophy; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor; Dopamine Receptor; Embryonic Development; Environment; Epilepsy; Equilibrium; Family; Future; Genes; Genetic; Genetic Research; Genetic study; Genetically Engineered Mouse; Goals; Grant; Human; Human Genetics; Hyperactive behavior; Individual; Intellectual functioning disability; Ion Channel; Journals; Knowledge; Laboratories; Lead; Learning; LoxP-flanked allele; Mass Spectrum Analysis; Membrane Proteins; Mentors; Methods; Methyl-CpG-Binding Protein 2; Modeling; Molecular; Moods; Motor; Motor Activity; Mus; Mutant Strains Mice; Mutation; Neurodevelopmental Disorder; Neurons; Neurosciences; Neurotransmitter Receptor; Patient Care; Patients; Pediatric Neurology; Pharmacology; Phelan-McDermid syndrome; Phenotype; Population; Protein Isoforms; Proteins; Proteomics; Receptor Signaling; Research; Research Personnel; Research Technics; Role; Seizures; Signal Transduction; Social Interaction; Symptoms; Synapses; Synaptic plasticity; Techniques; Technology; Testing; Therapeutic Effect; Training; Training Programs; Transcript; Transgenes; Viral; Work; Writing; autism spectrum disorder; behavior test; career; career development; density; design; disease-causing mutation; experience; genetic approach; in vivo; insight; interest; loss of function; loss of function mutation; medical specialties; meetings; motor deficit; motor impairment; motor learning; mouse model; nervous system disorder; neuronal circuitry; neurophysiology; novel; overexpression; postnatal period; postsynaptic; public health relevance; repetitive behavior; research study; response; skills; synaptic function; synaptogenesis; therapeutic evaluation; tool; translational neuroscience

 DESCRIPTION (provided by applicant): This proposal describes a five-year career development training program designed to lead to an independent academic career in translational neuroscience. Applicant: The applicant holds an M.D. and Ph.D. degree, and has completed specialty training in both Pediatrics and Child Neurology. He has previous experience with human genetics research and developing mouse models of neurologic disease. The career development plan includes a period of mentored research aimed at developing basic neuroscience knowledge and techniques that will greatly enhance his previous training and allow him to develop independence. The training will include learning research techniques and concepts supplemented by didactic training, seminars, lab meetings, journal clubs, national meetings, an advisory committee and meetings with the mentor. The research environment provides the best intellectual environment and the best technology available and gives the applicant the opportunity to be guided in learning powerful laboratory techniques. In addition to developing laboratory skills, the career development plan includes didactic training in grant writing and responsible conduct in research. Research plan: Disorders of function of the post-synaptic protein encoding gene called SHANKs are a new and growing area of scientific interest. Deficiency of SHANK3 causes Phelan-McDermid Syndrome (PMS) which is an autism spectrum disorder. He recently determined that duplications in humans and overexpression in mice also leads to neurodevelopmental symptoms. In this proposal, the applicant aims to investigate the neuronal and molecular mechanisms contributing to the Shank3 overexpression phenotype by genetic and chemo genetic methods to reverse the motor phenotype of these mice. He has used unbiased proteomic approach to investigate the molecular mechanisms driving the overexpression phenotype and identified a novel connection between Shank3 and dopamine receptor signaling.

 描述（由申请人提供）：本提案描述了一个为期五年的职业发展培训计划，旨在导致在转化神经科学的独立学术生涯。申请人：申请人持有医学博士学位。和博士学位，并已完成儿科和儿童神经病学的专业培训。他以前有人类遗传学研究和开发神经疾病小鼠模型的经验。职业发展计划包括一段时间的指导研究，旨在发展基本的神经科学知识和技术，这将大大提高他以前的培训，并使他能够发展独立性。培训将包括学习研究技术和概念，辅以教学培训、研讨会、实验室会议、期刊俱乐部、全国会议、咨询委员会和与导师的会议。研究环境提供了最好的知识环境和最好的技术，并为申请人提供了学习强大的实验室技术的指导机会。除了发展实验室技能外，职业发展计划还包括撰写赠款和负责任地进行研究的教学培训。研究计划：突触后蛋白编码基因SHANKs的功能障碍是一个新的和不断增长的科学兴趣领域。SHANK 3的缺乏会导致一种自闭症谱系障碍的M-M综合征（PMS）。他最近确定，人类的复制和小鼠的过度表达也会导致神经发育症状。在该提案中，申请人旨在通过遗传和化学遗传学方法研究促成Shank 3过表达表型的神经元和分子机制，以逆转这些小鼠的运动表型。他使用无偏见的蛋白质组学方法来研究驱动过表达表型的分子机制，并确定了Shank 3和多巴胺受体信号传导之间的新联系。

项目成果

The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss-of-function mutations.

• DOI: 10.1111/epi.13506
• 发表时间: 2016-10
• 期刊: Epilepsia
• 影响因子: 5.6
• 作者: Holder JL Jr;Quach MM
• 通讯作者: Quach MM

Exonic deletion of SLC9A9 in autism with epilepsy.

• DOI: 10.1212/nxg.0000000000000062
• 发表时间: 2016-04
• 期刊: Neurology. Genetics
• 作者: Cardon M;Evankovich KD;Holder JL Jr
• 通讯作者: Holder JL Jr

Two de novo novel mutations in one SHANK3 allele in a patient with autism and moderate intellectual disability.

• DOI: 10.1002/ajmg.a.38622
• 发表时间: 2018-04
• 期刊: American journal of medical genetics. Part A
• 作者: Zhu W;Li J;Chen S;Zhang J;Vetrini F;Braxton A;Eng CM;Yang Y;Xia F;Keller KL;Okinaka-Hu L;Lee C;Holder JL Jr;Bi W
• 通讯作者: Bi W