Minority Predoctoral Fellowship Program

少数族裔博士前奖学金计划

• 批准号: 7878063
• 负责人: QUENTIN J BACA
• 金额: $ 4.14万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878063
• 关键词: 1-Phosphatidylinositol 3-Kinase; Actins; Address; Ankyrins; Antibodies; Antigens; Anus; Area; Arts; Autoimmune Diseases; Award; Basic Science; Binding; Biochemical; Biochemistry; Biological; Biological Models; Cell Line; Cell Mobility; Cell membrane; Cell model; Cells; Characteristics; Chemistry; Cholesterol; Colchicine; Communicable Diseases; Cytochalasins; Cytoskeletal Proteins; Cytoskeleton; Data; Development; Diffusion; Doctor of Philosophy; Effector Cell; Elements; Environment; Enzymes; Equilibrium; Faculty; Fellowship Program; Fluorescence Recovery After Photobleaching; Future; General Qualifier; Goals; Grant; Human; Image; Immune; Immune response; Immune system; Individual; Infection; Institution; Interphase Cell; Journals; Lateral; Lead; Letters; Lipids; Malignant Neoplasms; Measurement; Measures; Membrane; Membrane Fluidity; Membrane Microdomains; Membrane Proteins; Mentors; Methods; Microtubules; Minority; Modeling; Molecular; Motion; Oncogenic; PTPRC gene; Pattern; Pharmacology; Physicians; Population; Positioning Attribute; Preparation; Process; Protein Tyrosine Phosphatase; Proteins; Proteomics; Public Health; Publications; Recommendation; Regulation; Research; Resolution; Rest; Role; Rotation; Science; Scientist; Screening procedure; Signal Transduction; Solid; Specific qualifier value; Spectrin; Students; System; T-Cell Activation; T-Lymphocyte; Talents; Techniques; Testing; Time; Tissues; Training; Training Programs; Transfection; Tubulin; United States National Institutes of Health; Universities; Update; Work; Writing; base; career; clinical application; effective therapy; experience; graduate student; improved; inhibitor/antagonist; insight; interest; jasplakinolide; leukemia; medical schools; meetings; millisecond; nanometer; nanoscale; novel; particle; polymerization; pre-doctoral; professor; programs; receptor; response; single molecule; spelling

DESCRIPTION (provided by applicant): The focus of this proposal is to investigate biologically important mechanisms of membrane receptor mobility regulation and how they relate to T cell activation in the human immune system. Specifically, we will examine the mobility control mechanisms and molecular associations of the receptor-like tyrosine phosphatase CD45, a key regulator of T cell activation. CD45 is necessary for T cell stimulation by antigen, and this requirement involves the dynamic regulation of CD45 mobility. There is biochemical evidence that populations of CD45 reside in lipid microdomains and associate with the cytoskeleton, and it is proposed that these interactions regulate CD45 function. To better understand the dynamic regulation of CD45, we will characterize this receptor's lateral mobility in a T cell model using high-resolution single-molecule techniques. We will measure the effects on CD45 mobility of cell activation and of pharmacological inhibitors predicted to disrupt CD45 molecular interactions (e.g., cytochalasin, jasplakinolide, colchicine). We will also investigate the role of specific molecular partners (e.g., spectrin, ankyrin) in CD45 mobility regulation. Together, these studies will provide a detailed molecular picture of CD45 interactions and function and provide insight into general mechanisms of receptor mobility regulation. Relevance of research to public health: Among other functions, the human immune system protects our bodies from a variety of infections. In order to perform these functions effectively without causing damage to body tissues, the immune system must maintain a delicate balance in which immune effector cells (for example, T cells) are activated only when needed. The specific molecular mechanisms that allow the activation of T cells are not completely understood, but it is clear that a critical aspect of activation is the regulation of receptor mobility in the plane of the T cell membrane. The focus of this proposal is to investigate biologically important mechanisms of membrane receptor mobility regulation and how they relate to T cell activation in the human immune system. Improved understanding of this process is likely to lead to safer and more effective therapies for infectious diseases, autoimmune diseases, and cancer. Introduction to Revised application: This is a revised application which is now on its second submission. In response to the previous review, the applicant, Quentin Baca, has revised the research plan to address criticisms that it was overly ambitious and that the biological problem to be addressed was poorly specified. There were also concerns that recent publications by the mentor were not as the corresponding author and that the mentor did not adequately spell out a detailed training plan for the Applicant. Applicant's Preparation for Graduate Study: As noted in the previous review, Mr. Baca is a promising student. His undergraduate record at Stanford in the sciences was generally excellent and he received a BS in chemistry in 2004. Almost all the courses taken at Harvard in the MD/PhD program were Medical School courses that were only offered on a pass fail basis and these grades were all P's. In three of the graduate courses at Harvard Mr. Baca received A's. The MCAT scores were excellent. The applicant's undergraduate research experience was in the Zare lab studying attachment of biologically active enzymes to a solid support matrix. This work resulted in a publication in Anal. Chem. on which he was a middle author. Mr. Baca has received numerous awards for his undergraduate work. At Harvard Mr. Baca did 2 rotations first in Thomas Look's lab working on making antibodies to oncogenic transfection factors involved in Human leukemias and then in Dr. David Golan's lab studying transmembrane receptor mobility. This will be the subject of his PhD thesis work. The letters of recommendation are very strong and attest to the applicant's talents as a creative future physician-scientist. The Quality of the Training Program/Institution: The environment at the Harvard Medical School will provide the applicant with an outstanding environment for the combined MD-PhD degree. Dr. Golan's lab will provide excellent facilities for the proposed work involving demanding single particle tracking techniques required for his thesis project. Additional facilities include the Imaging Center at the Medical School. Numerous seminars and journal clubs and opportunities for the applicant to present his work are also available. To address a concern in the previous review, the revised application states more explicitly how the mentor through frequent meetings will be involved in Mr. Baca's training. The Proposed Research: In the previous review of this application there were concerns that some parts of the application were overly ambitious and that the scientific problem to be addressed was not clearly stated. In response the applicant has revised Aim 3 to narrow the number of CD45 interaction partners to a study of 1-3 cytoskeletal proteins. He has also more explicitly stated the significance of the biological problem to be studied as how cells control transmembrane receptor mobility. The applicant will use technologically sophisticated single particle tracking of individual receptors to examine how mobility of CD45, a receptor which is a key regulator of T cell activation, is differentially regulated in resting vs. activated T cells. Using as a model system, the Jurkat T cell line, the applicant has interesting data for aim 1 to show the feasibility of these approaches and for aim 2 preliminary evidence that CD45 lateral mobility in the membrane is regulated by association with the spectrin-ankyrin cytoskeleton. He will experimentally examine associations of the CD45 receptor with other cytoskeletal elements such as actin and microtubules to test their role in regulation of receptor mobility. In aim 3 the applicant will use proteomic screening to identify several interaction proteins that associate differentially with CD45 in activated and resting T cells. This is a well laid out proposal to address an important question regarding molecular mechanisms by which CD45 modulates the immune response. Given the quality of the preliminary data and the expertise available in Dr. Golan's lab, the applicant is likely to produce an excellent thesis that will provide an outstanding training experience. The Thesis Mentor: In response to concerns about the mentor's recent publications as corresponding author, the revised application has updated Dr. Golan's CV. Dr. Golan has had a productive 20 year career on the Harvard faculty where he is a Professor of Biological Chemistry and Molecular Pharmacology. His publications in the area of protein and lipid mobility in cell membranes have appeared in high profile journals and he has received an NIH MERIT award which terminated in March 2007. It is not mentioned whether this grant will be renewed. Dr. Golan has trained 18 postdocs and 12 graduate students and 4 of the 5 students listed have tenure track faculty positions at research universities. The mentor has also been a Co-director of the Harvard MD-PhD program. Overall Recommendation: This is a well written application that addresses the concerns of the previous review. The goals of the work are clearly stated and the mentor provides a more detailed training program. The applicant is an excellent candidate for this award and has outstanding potential to combine basic science with clinical applications as an MD-PhD.

描述（由申请人提供）：本提案的重点是研究膜受体迁移性调节的生物学重要机制以及它们与人类免疫系统中 T 细胞激活的关系。具体来说，我们将检查受体样酪氨酸磷酸酶 CD45（T 细胞激活的关键调节因子）的移动性控制机制和分子关联。 CD45对于抗原刺激T细胞是必需的，这一要求涉及CD45迁移率的动态调节。有生化证据表明 CD45 群体存在于脂质微结构域中并与细胞骨架相关，并且有人提出这些相互作用调节 CD45 功能。为了更好地理解 CD45 的动态调节，我们将使用高分辨率单分子技术在 T 细胞模型中表征该受体的横向移动性。我们将测量细胞激活和预测破坏 CD45 分子相互作用的药理学抑制剂（例如细胞松弛素、jasplakinolide、秋水仙碱）对 CD45 迁移率的影响。我们还将研究特定分子伴侣（例如血影蛋白、锚蛋白）在 CD45 迁移率调节中的作用。总之，这些研究将提供 CD45 相互作用和功能的详细分子图景，并深入了解受体迁移率调节的一般机制。研究与公共卫生的相关性：除其他功能外，人体免疫系统还可以保护我们的身体免受各种感染。为了有效地执行这些功能而不会对身体组织造成损害，免疫系统必须保持微妙的平衡，其中免疫效应细胞（例如 T 细胞）仅在需要时才被激活。 T 细胞激活的具体分子机制尚不完全清楚，但很明显激活的一个关键方面是 T 细胞膜平面内受体迁移性的调节。该提案的重点是研究膜受体迁移性调节的生物学重要机制以及它们与人类免疫系统中 T 细胞激活的关系。加深对这一过程的了解可能会为传染病、自身免疫性疾病和癌症提供更安全、更有效的治疗方法。 修改后的申请简介： 这是修改后的申请，现已第二次提交。为了回应之前的审查，申请人昆汀·巴卡（Quentin Baca）修改了研究计划，以回应对其过于雄心勃勃以及要解决的生物学问题不明确的批评。还有人担心导师最近发表的论文不是通讯作者，而且导师没有充分阐明申请人的详细培训计划。 申请人的研究生学习准备：正如之前的评论中所指出的，Baca 先生是一位有前途的学生。他在斯坦福大学的理科本科成绩总体上非常出色，并于 2004 年获得了化学学士学位。在哈佛大学的医学博士/博士项目中，几乎所有课程都是医学院课程，只提供及格不及格的基础，这些成绩都是 P。巴卡先生在哈佛大学的三门研究生课程中获得了 A 的成绩。 MCAT 成绩非常出色。申请人的本科研究经历是在 Zare 实验室研究生物活性酶与固体支持基质的附着。这项工作发表在《肛门》杂志上。化学。他是其中的中间作者。巴卡先生因其本科工作而获得了无数奖项。在哈佛大学，Baca 先生进行了两次轮转，首先在 Thomas Look 的实验室工作，致力于制造针对人类白血病的致癌转染因子的抗体，然后在 David Golan 博士的实验室研究跨膜受体的迁移性。这将是他的博士论文工作的主题。推荐信非常有力，证明了申请人作为一名富有创造力的未来医师科学家的才能。 培训项目/机构的质量：哈佛医学院的环境将为申请人提供获得医学博士-博士学位联合学位的卓越环境。 Golan 博士的实验室将为拟议的工作提供优良的设施，其中涉及他的论文项目所需的高要求的单粒子跟踪技术。其他设施包括医学院的影像中心。申请人还可以参加许多研讨会和期刊俱乐部以及展示其作品的机会。为了解决之前审查中的问题，修订后的申请更明确地说明了导师将如何通过频繁的会议参与 Baca 先生的培训。 拟议的研究：在之前对该申请的审查中，有人担心该申请的某些部分过于雄心勃勃，并且没有明确说明要解决的科学问题。作为回应，申请人修改了目标 3，将 CD45 相互作用伴侣的数量缩小到 1-3 种细胞骨架蛋白的研究。他还更明确地阐述了细胞如何控制跨膜受体迁移性这一生物学问题的重要性。申请人将使用技术先进的单粒子追踪单个受体来检查 CD45（T 细胞激活的关键调节受体）的移动性在静息 T 细胞与激活 T 细胞中的差异调节方式。使用 Jurkat T 细胞系作为模型系统，申请人获得了目标 1 的有趣数据，以显示这些方法的可行性，并获得了目标 2 的初步证据，即 CD45 在膜中的横向移动性是通过与血影蛋白锚蛋白细胞骨架的关联来调节的。他将通过实验检查 CD45 受体与肌动蛋白和微管等其他细胞骨架元件的关联，以测试它们在调节受体迁移性中的作用。在目标 3 中，申请人将使用蛋白质组学筛选来鉴定与活化和静息 T 细胞中的 CD45 差异相关的几种相互作用蛋白。这是一个精心设计的提案，旨在解决有关 CD45 调节免疫反应的分子机制的重要问题。鉴于初步数据的质量和 Golan 博士实验室提供的专业知识，申请人很可能写出一篇优秀的论文，从而提供出色的培训经验。 论文导师：为了回应对导师最近作为通讯作者发表的出版物的担忧，修改后的申请更新了 Golan 博士的简历。 Golan 博士在哈佛大学拥有 20 年富有成效的职业生涯，担任生物化学和分子药理学教授。他在细胞膜中蛋白质和脂质流动性领域的出版物发表在知名期刊上，并获得了 NIH MERIT 奖，该奖于 2007 年 3 月终止。没有提及是否会续签该资助。 Golan 博士培养了 18 名博士后和 12 名研究生，所列 5 名学生中有 4 名在研究型大学担任终身教职。这位导师也是哈佛大学医学博士项目的联合主任。 总体建议：这是一个写得很好的应用程序，解决了之前审查的问题。工作目标明确，导师提供更详细的培训计划。申请人是该奖项的优秀候选人，作为医学博士-博士具有将基础科学与临床应用相结合的杰出潜力。