Minority Predoctoral Fellowship Program

少数族裔博士前奖学金计划

• 批准号: 7409826
• 负责人: QUENTIN J BACA
• 金额: $ 4.1万
• 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/7409826
• 关键词: 1-Phosphatidylinositol 3-Kinase; 5-(4-hydroxy-3-methoxyphenyl)-5-phenylhydantoin; 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; Condition; 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; Numbers; Oncogenic; PTPRC gene; Pattern; Pharmacology; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Physicians; Population; Positioning Attribute; Preparation; Process; Protein Tyrosine Phosphatase; Proteins; Proteomics; Public Health; Publications; Rate; Recommendation; Regulation; Research; Resolution; Rest; Role; Rotation; Science; Scientist; Score; 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; experience; improved; inhibitor/antagonist; insight; interest; jasplakinolide; leukemia; medical schools; 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）：该提案的重点是研究膜受体迁移率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。具体而言，我们将研究T细胞活化的关键调节剂，迁移性控制机制和分子关联。 CD45对于通过抗原刺激T细胞是必需的，该需求涉及CD45迁移率的动态调节。有生化证据表明，CD45的种群驻留在脂质微区域并与细胞骨架相关，并提出这些相互作用调节CD45功能。为了更好地了解CD45的动态调节，我们将使用高分辨率的单分子技术在T细胞模型中表征该受体的横向迁移率。我们将衡量对细胞活化的CD45迁移率和预测会破坏CD45分子相互作用（例如，细胞切拉蛋白，jasplakinolide，corchicine）的影响。我们还将研究特定分子伙伴（例如Spectrin，Ankyrin）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，并洞悉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，人类免疫系统可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损害人体组织，免疫系统必须保持微妙的平衡，在这种平衡中，仅在需要时才激活免疫效应细胞（例如T细胞）。允许T细胞激活的特定分子机制尚未完全了解，但是很明显，激活的关键方面是调节T细胞膜平面中受体迁移率。该建议的重点是研究膜受体迁移率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。对这一过程的了解的提高可能会导致有关传染病，自身免疫性疾病和癌症的更安全，更有效的疗法。 修订申请简介：这是一个修订的应用程序，现在已在其第二次提交中。为了回应先前的审查，申请人昆汀·巴卡（Quentin Baca）修订了研究计划，以解决批评它过于雄心勃勃，并且要解决的生物学问题被指定很差。人们还担心，导师的最新出版物不是作为相应的作者，而导师没有充分阐明申请人的详细培训计划。 申请人的研究生研究准备：如先前的评论中所述，巴卡先生是一名有前途的学生。他在科学斯坦福大学（Stanford）的本科纪录通常非常出色，他在2004年获得了化学学士学位。在哈佛大学（Harvard/PhD）课程中，几乎所有在MD/博士学位课程中所学的课程都是医学院课程，这些课程仅在通过失败的基础上提供，这些等级都是P。在哈佛大学的三个研究生课程中，巴卡先生接受了A。 MCAT分数很棒。申请人的本科研究经验是在Zare Lab研究生物活性酶与固体支持基质的附着。这项工作导致了肛门的出版物。化学他是中间作者。巴卡先生因其本科工作而获得了许多奖项。在哈佛大学，巴卡先生在托马斯·莱克（Thomas Look）的实验室首先进行了两次旋转，致力于制造与人类白血病有关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迁移率的实验室中。这将是他博士学位论文工作的主题。推荐信非常强烈，并证明了申请人的才华，作为创造性的未来医师科学家。 培训计划/机构的质量：哈佛医学院的环境将为申请人提供良好的MD-PHD学位环境。 Golan博士的实验室将为涉及其论文项目所需的单个粒子跟踪技术的拟议工作提供出色的设施。其他设施包括医学院的成像中心。还提供许多研讨会和期刊俱乐部以及申请人展示其作品的机会。为了解决先前审查的关注，修订后的应用程序更明确地指出了如何通过BACA先生的培训涉及频繁会议的导师。 拟议的研究：在对本申请的先前综述中，人们担心该应用程序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。作为响应，申请人修改了目标3，以将CD45相互作用伙伴的数量缩小到1-3个细胞骨架蛋白的研究。他还更加明确地说明了生物学问题的重要性，以研究细胞如何控制跨膜受体迁移率。申请人将使用技术复杂的单个受体跟踪的技术复杂的单个粒子跟踪来检查CD45的迁移率是T细胞激活的关键调节剂CD45的迁移率如何在静止与活化的T细胞中受到差异调节。申请人使用作为模型系统，即Jurkat T细胞系，具有有趣的AIM 1数据，以证明这些方法的可行性，并且AIM 2初步证据表明，膜中CD45横向迁移率与Spectrin-ankyrin-ankyrin cytoskeTskeleton相关。他将通过实验检查CD45受体与其他细胞骨架元素（如肌动蛋白和微管）的关联，以测试其在调节受体迁移率中的作用。在AIM 3中，申请人将使用蛋白质组学筛选来识别几种相互作用的蛋白质，这些相互作用蛋白与激活和静止的T细胞中的CD45差异化。这是一个很好的建议，可以解决有关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博士实验室中可用的专业知识，申请人可能会提供出色的论文，从而提供出色的培训经验。 论文导师：回应有关导师最近作为通讯作者出版的关注，修订后的申请已更新了Golan博士的简历。戈兰博士在哈佛学院担任生物化学和分子药理学教授的20年职业生涯。他在细胞膜中蛋白质和脂质流动性领域的出版物出现在备受瞩目的期刊上，他获得了2007年3月终止的NIH优点奖。没有提到该赠款是否会续签。戈兰博士已经培训了18个博士后和12名研究生，而被列出的5名学生中有4名在研究型大学担任过任期教师职位。这位导师也是哈佛MD-PHD计划的联合导演。 总体建议：这是一个写得很好的应用程序，可以解决上一篇评论的关注点。明确指出了工作的目标，导师提供了更详细的培训计划。申请人是该奖项的绝佳候选人，并且具有将基础科学与MD-PHD临床应用相结合的杰出潜力。