Analysis of Immune Responses in Inflammatory Bowel Disease by Immuno-PET

通过免疫 PET 分析炎症性肠病的免疫反应

• 批准号: 7787037
• 负责人: Bittoo Kanwar
• 金额: $ 14.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-08 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787037
• 关键词: Address; Adoptive Transfer; Adverse effects; Affect; Age; American; Animal Model; Antibodies; Applications Grants; Architecture; Area; Award; B-Lymphocytes; Basic Science; Biology; CD4 Positive T Lymphocytes; California; Cancer Diagnostics; Cell Count; Cell Density; Cells; Childhood; Clinic; Clinical; Clinical Data; Clinical Medicine; Clinical Trials; Colitis; Communicable Diseases; Crohn' s disease; Data; Detection; Development; Diagnosis; Disease; Disease Progression; Disease model; Disease remission; Endoscopic Biopsy; Evaluation; Event; Fab Immunoglobulins; Fibrosis; Fluorine; Foundations; Funding; Future; Gastroenterologist; Gastroenterology; General Population; Goals; HIV Infections; Hepatology; Histopathology; Homing; Human; Image; Image Analysis; Imagery; Imaging Techniques; Immune; Immune response; Immunohistochemistry; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Investigation; Kinetics; Knowledge; Label; Lead; Learning; Ligands; Location; Lymphocyte; Malignant Neoplasms; Mediating; Medical; Medicine; Mentors; Methods; Modality; Modeling; Monitor; Monoclonal Antibodies; Mucosal Immune Responses; Mucositis; Mus; Opportunistic Infections; Pathogenesis; Pathology; Patients; Peptides; Pharmaceutical Preparations; Population; Positron-Emission Tomography; Process; Protein Fragment; Proteins; Radio; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Regression Analysis; Research; Research Personnel; Resources; Risk; Role; SCID Mice; SCID-hu Mice; Safety; Sample Size; San Francisco; Senior Scientist; Series; Severities; Severity of illness; Signal Transduction; Signs and Symptoms; Specificity; Staging; Surface; Techniques; Technology; Testing; Therapeutic; Time; Titrations; Tracer; Training; Translating; Translational Research; Translations; Tuberculosis; Ulcerative Colitis; Universities; Xenograft procedure; adalimumab; antibody conjugate; base; career; career development; clinical practice; design; dosimetry; experience; fetal; glucose analog; human disease; human subject; image reconstruction; imaging modality; immunogenic; improved; in vivo; infliximab; insight; lymph nodes; mouse model; natalizumab; novel; nutrition; public health relevance; radiotracer; response; single photon emission computed tomography; skills; technique development; tool; treatment strategy; uptake

DESCRIPTION (provided by applicant): This is an application for a K08 award for Dr. Bittoo Kanwar, a fellow in pediatric gastroenterology, hepatology, and nutrition at the University of California, San Francisco, who is establishing himself as a young investigator in non-invasive means to study the immune response in inflammatory bowel disease (IBD). This K08 award will provide Dr. Kanwar with the support necessary to accomplish the following goals: (1) to gain expertise in the utility of antibody-based PET (immuno-PET) in IBD; (2) using these novel non-invasive modalities, correlate those findings with biologic processes occurring in vivo at the mucosal surface; (3) to optimize these methods and test their efficacy and sensitivity on human cells prior to ultimate translation to human subjects; and (4) to develop an independent research career as a translational investigator. To achieve these goals, Dr. Kanwar has assembled a mentoring team comprised of a primary mentor, Dr. Joseph "Mike" McCune, Chief of the Division of Experimental Medicine at UCSF, who conducts basic and translational research in infectious disease and inflammatory disorders (in particular HIV infection), and three co-mentors: Dr. Melvin B. Heyman, a pediatric gastroenterologist with expertise in the translational and clinical investigation of IBD; Dr. Averil Ma, director of The Colitis and Crohn's Disease Center at UCSF; and Dr. Simon Williams, a Senior Scientist at Genentech, Inc., and an expert in PET imaging and analysis of various inflammatory conditions, including IBD. Technologies to quantitate the mucosal immune response in vivo in a non-invasive manner is [sic] essential to understanding disease pathogenesis and response to therapy in both small animal models and human patients alike. These studies are proposed to answer the question: is it possible to quantitate and visualize specific subpopulations of immune cells implicit in disease pathogenesis in IBD? Dr. Kanwar will leverage the resources available at both UCSF and Genentech to: determine the extent to which specific subpopulations of murine immune cells can be detected in vivo using radiolabeled monoclonal antibodies and Fab fragments (Aim 1), determine the sensitivity of immuno-PET in the context of murine IBD (Aim 2), and to extend these technologies to the visualization and quantitation of human cells in the heterochimeric SCID-hu Thy/Liv/LN mouse - a mouse model with circulating and functional human immune cells (Aim 3). This will provide Dr. Kanwar the necessary skills and preliminary data in which these imaging agents and technologies, optimized during the course of the 5-year K08 award period, can be translated to human subjects as an R01 grant application. PUBLIC HEALTH RELEVANCE: Improving the understanding of cell-specific immune responses in IBD in a non-invasive in vivo manner will be critical to the development and testing of future therapies, both in basic science research and clinical practice. The optimization of these technologies will impact the medical burden that IBD has placed on the public as whole as novel imaging modalities will expand our knowledge about IBD and lead to appropriate - and cell specific - treatment strategies.

描述（由申请人提供）： 这是 Bittoo Kanwar 博士申请 K08 奖的申请，Bittoo Kanwar 博士是旧金山加利福尼亚大学儿科胃肠病学、肝病学和营养学研究员，正在以非侵入性手段研究免疫学，成为一名年轻的研究者。炎症性肠病（IBD）的反应。 K08 奖项将为 Kanwar 博士提供实现以下目标所需的支持：(1) 获得基于抗体的 PET（免疫 PET）在 IBD 中的应用方面的专业知识； (2) 使用这些新颖的非侵入性方式，将这些发现与体内粘膜表面发生的生物过程相关联； (3) 优化这些方法并在最终转化为人类受试者之前测试它们对人类细胞的功效和敏感性； (4) 作为转化研究者发展独立的研究生涯。为了实现这些目标，坎瓦尔博士组建了一个指导团队，由主要导师、加州大学旧金山分校实验医学部主任 Joseph“Mike”McCune 博士组成，他在传染病和炎症性疾病方面进行基础和转化研究。以及三位共同导师：Melvin B. Heyman 博士，一位儿科胃肠病学家，在 IBD 转化和临床研究方面拥有专业知识； Averil Ma 博士，加州大学旧金山分校结肠炎和克罗恩病中心主任； Simon Williams 博士是 Genentech, Inc. 的高级科学家，也是各种炎症性疾病（包括 IBD）的 PET 成像和分析专家。 以非侵入性方式定量体内粘膜免疫反应的技术对于了解小动物模型和人类患者的疾病发病机制和治疗反应至关重要。这些研究旨在回答以下问题：是否有可能对 IBD 疾病发病机制中隐含的特定免疫细胞亚群进行定量和可视化？ Kanwar 博士将利用 UCSF 和 Genentech 的可用资源来：确定使用放射性标记的单克隆抗体和 Fab 片段在体内检测小鼠免疫细胞特定亚群的程度（目标 1），确定免疫 PET 的敏感性在小鼠 IBD 的背景下（目标 2），并将这些技术扩展到异嵌合 SCID-hu Thy/Liv/LN 小鼠中人类细胞的可视化和定量 - a具有循环和功能性人类免疫细胞的小鼠模型（目标 3）。这将为 Kanwar 博士提供必要的技能和初步数据，这些显像剂和技术在 5 年 K08 奖励期内得到优化，可以作为 R01 拨款申请转化为人类受试者。 公共卫生相关性： 以非侵入性体内方式提高对 IBD 细胞特异性免疫反应的理解对于基础科学研究和临床实践中未来疗法的开发和测试至关重要。这些技术的优化将影响 IBD 给公众带来的医疗负担，因为新颖的成像方式将扩大我们对 IBD 的了解，并导致适当的细胞特异性治疗策略。