Multimodal Biomarkers in Frontotemporal Lobar Degeneration

描述（由申请人提供）：这个K01奖将支持我作为一个独立的研究者与翻译研究计划，专门从事神经退行性疾病，如额颞叶变性（FTLD）的认知和生物学基础的发展。候选人：作为一名认知神经科学家，我的研究经验使我能够实现我的职业目标，成为一名独立的研究人员，在神经退行性疾病的认知和生物学基础上具有专业知识。我有很强的认知训练与心理语言学硕士和心理学博士从爱丁堡大学，在那里我是由NRSA个人博士前奖的支持。在宾夕法尼亚大学认知科学研究所的IGERT博士后研究期间，我被授予NRSA个人博士后研究金，以调查语言决策的作用。在这项研究中，我获得了经验，调查神经退行性疾病患者比较，以获得收敛的证据，以补充健康成人的功能磁共振成像研究。我越来越有兴趣将我的研究转化为优化神经退行性疾病患者的诊断和治疗。我最近被授予语言神经生物学博士后优异奖，以表彰我的新研究，调查患者的社会限制如何导致话语困难。我已经承诺了四年的临床研究NIH贷款偿还计划，我打算在我的职业生涯中致力于临床研究。我了解到，认知和神经影像学研究只能提供神经退行性疾病的一个视角。在这项提案中，我计划获得FTLD和相关条件的生物学方面的必要专业知识，以补充我过去的经验，从而实现我成为一名多方面的独立研究者的目标，在神经退行性疾病的认知和生物学基础方面具有专业知识。在这个K01的支持下，我将发展专业知识，进行脑脊液（CSF），遗传和神经退行性疾病的神经病理学方面的调查。我最终将把这项提议中获得的生物学专业知识与我的认知神经科学研究中的语言研究相结合，以确定可用于筛选临床试验患者的非侵入性生物标志物，并测量疾病修饰剂的疗效。工作环境：该奖项将在宾夕法尼亚大学佩雷尔曼医学院神经病学系、神经退行性疾病研究中心（CNDR）和宾夕法尼亚生物信息学中心进行，我在那里有强大的机构支持。拟议的机构是一个特殊的环境，拥有神经影像学，脑脊液生物标志物分析，领先的遗传研究核心，专家神经病理学，杰出的生物医学支持和相关的临床研究实验室的专家中心。宾夕法尼亚大学与该国其他机构相比是独一无二的，因为所有上述方法都可以在一个中心使用。我的导师Murray Grossman博士和我的共同导师John Trojanowksi博士在神经退行性疾病研究方面享有国际声誉。我的职业发展也将得到我的共同导师Lyle Ungar博士的支持，他在统计学习算法以及蛋白质组学和基因组学数据集分析方面拥有丰富的专业知识。总之，这个导师团队将通过提供现有和未来的合作者，实验室资源和特殊的培训环境来促进我作为独立调查员的发展。CNDR是世界领先的神经退行性疾病研究中心，拥有人类和动物疾病模型以及卓越的转化科学。生物流体生物标志物的经验是广泛的，几个国家的生物流体核心集中在宾夕法尼亚州（如ADNI）。宾夕法尼亚大学的宾夕法尼亚成像和计算机科学实验室拥有丰富的国际公认的神经成像专业知识，我将通过将这些设施的神经成像资源与其他生物标志物研究模式相结合而受益。培训内容：我将在我的导师Murray Grossman博士和我的共同导师John Trojanowski博士和Lyle Ungar博士的支持下发展我在神经退行性疾病生物学基础方面的专业知识。具体来说，我将与Trojanowksi博士一起参加与FTLD的生物流体和遗传生物标志物相关的培训。我将与Ungar博士一起发展先进的神经成像技能和尖端的生物统计方法。每一种培训模式都将得到补充的正式课程、参加研讨会、出席会议以及与辅导小组定期举行会议的支持。研究：FTLD是一种神经退行性疾病，影响约15/100，000人。近年来，尸检中详细的神经病理学研究已经证明了FTLD组织病理学异常的不同来源，包括tau内含物（FTLD-tau）和TDP-43蛋白病（FTLD-TDP）的存在。然而，目前没有用于区分FTLD-tau和FTLD-TDP的体内方法。迫切需要改善FTLD的体内诊断，以使患者适当地进入新兴的临床试验，并在试验中开发敏感和特异性终点，以量化对这些治疗的反应。该提案的总体研究目标是开发多模式方法以改善FTLD的体内诊断。

DESCRIPTION (provided by applicant): This K01 award will support my development as an independent investigator with a translational research program that specializes in the cognitive and biological basis of neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD). Candidate: My research experience as a cognitive neuroscientist ideally positions me to achieve my career goal of becoming an independent investigator with expertise on the cognitive and biological basis of neurodegenerative disease. I have strong cognitive training with an M.Sc in Psycholinguistics and Ph.D in Psychology from the University of Edinburgh, where I was supported by an NRSA Individual Predoctoral Award. During my postdoctoral IGERT fellowship at the Institute for Research in Cognitive Science at the University of Pennsylvania, I was awarded an NRSA Individual Postdoctoral Fellowship Award to investigate the role of decision-making in language. In this research I have gained experience investigating neurodegenerative disease patients comparatively in order to obtain converging evidence to complement fMRI studies of healthy adults. I have become increasingly interested in translating my research to optimize the diagnosis and treatment of patients with neurodegenerative diseases. I was recently award the Society for the Neurobiology of Language Postdoctoral Merit Award in recognition of my novel research investigating how social limitations in patients contribute to difficulty in discourse. I have committed to four years of clinical research the NIH Loan Repayment Program, and I intend to commit to clinical research for the duration of my career. I have learned that cognitive and neuroimaging studies provide only one perspective on neurodegenerative diseases. In this proposal, I plan to gain the necessary expertise in biological aspects of FTLD and related conditions to complement my past experiences, and thus achieve my goal of becoming a multifaceted independent investigator with expertise in the cognitive and biological basis for neurodegenerative diseases. With the support of this K01, I will develop expertise to conduct investigations of cerebrospinal fluid (CSF), genetic, and neuropathological aspects of neurodegenerative diseases. I will ultimately integrate the biological expertise gained in this proposal with language studies from my cognitive neuroscience research in an effort to identify non-invasive biomarkers that can be used to screen patients for clinical trials and to measure the efficacy of disease-modifying agents. Environment: This award will be conducted at the Perelman School of Medicine at the University of Pennsylvania in the Department of Neurology, the Center for Neurodegenerative Disease Research (CNDR), and the Penn Bioinformatics Center where I have strong institutional support. The proposed institution is an exceptional environment that has expert centers for neuroimaging, cerebrospinal fluid biomarker analysis, a leading genetic research core, expert neuropathology, outstanding biostatisical support, and relevant clinical research laboratories. The University of Pennsylvania is unique in comparison to other institutions in the country because all of the above methods are available in one center. My mentor, Dr. Murray Grossman, and my co-mentor, Dr. John Trojanowksi, have international reputations for neurodegenerative disease research. My career development will also be supported by my co-mentor, Dr. Lyle Ungar, who has extensive expertise in statistical learning algorithms and in the analysis of proteomic and genomics datasets. Together, this mentorship team will facilitate my development as an independent investigator by providing access to existing and future collaborators, laboratory resources, and exceptional training environments. The CNDR is a world- leading center for neurodegenerative disease research with human and animal models of disease and exceptional translational science. Biofluid biomarker experience is extensive, and several national biofluid cores are centered at Penn (e.g. ADNI). There is a wealth of internationally-recognized neuroimaging expertise at the University of Pennsylvania in the Penn Imaging and Computer Science Laboratory, and I will benefit by integrating neuroimaging resources from these facilities with other modalities of biomarker research. Training: I will develop my expertise in the biological basis of neurodegenerative disease with the support of my mentor, Dr. Murray Grossman, and my co-mentors, Dr. John Trojanowski and Dr. Lyle Ungar. Specifically, with Dr. Trojanowksi I will engage in training related to biofluid and genetic biomarkers of FTLD. I will develop advanced neuroimaging skills and cutting-edge biostatistical methods with Dr. Ungar. Each of these training modalities will be supported by complementary formal coursework, participation in seminars, attendance of conferences, and regularly scheduled meetings with mentorship team. Research: FTLD is a neurodegenerative disease affecting approximately 15 out of 100,000 individuals. In recent years detailed neuropathological investigations at autopsy have demonstrated distinct sources of histopathological abnormalities in FTLD, including the presence of tau inclusions (FTLD-tau) and TDP-43 proteinopathies (FTLD-TDP). However, there are currently no in vivo methods for discriminating between FTLD-tau and FTLD-TDP. There is an urgent need to improve the in vivo diagnosis of FTLD to appropriately enter patients into emerging clinical trials, and to develop sensitive and specific endpoints in trials that can quantify response to these treatments. The overall research aim of this proposal is to develop multimodal methods to improve in vivo diagnosis of FTLD.