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: 8021001
• 负责人: Bittoo Kanwar
• 金额: $ 14.55万
• 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 2012-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8021001
• 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 remission; Endoscopic Biopsy; Evaluation; Event; Fab Immunoglobulins; Fibrosis; Fluorine; Foundations; Funding; Future; Gastroenterologist; Gastroenterology; General Population; Goals; HIV Infections; Health; 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; 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; Signal Transduction; Signs and Symptoms; Specificity; Staging; Surface; T-Lymphocyte; TNF gene; Techniques; Technology; Testing; 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; 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）： 这是加利福尼亚大学旧金山分校的小儿胃肠病学，肝病学和营养的研究员Bittoo Kanwar博士申请K08奖。该K08奖将为Kanwar博士提供实现以下目标所需的支持：（1）在IBD中获得基于抗体的PET（Immuno-PET）的专业知识； （2）使用这些新型的非侵入性方式，将这些发现与粘膜表面体内发生的生物过程相关联； （3）在最终转化为人类受试者之前，要优化这些方法并测试其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职业。 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 IBD的调查； UCSF结肠炎和克罗恩病中心主任Averil Ma博士； Genentech，Inc。的高级科学家西蒙·威廉姆斯（Simon Williams）博士，以及包括IBD在内的各种炎症状况的宠物成像和分析专家。 以非侵入性方式定量体内粘膜免疫反应的技术对于理解小动物模型和人类患者的疾病发病机理和对治疗的反应至关重要。提出了这些研究来回答以下问题：是否可以定量和可视化IBD疾病发病机理中隐含的免疫细胞的特定亚群？ Kanwar博士将利用UCSF和GenEntech的可用资源来确定：确定可以在多大程度上使用辐射标记的单克隆抗体和FAB片段在体内检测到鼠免疫细胞的特定亚群（AIM 1），并确定量子的敏感性，以扩展这些技术的敏感性，以扩展这些技术和量子的影响。杂化聚体Scid -hu/liv/ln小鼠 - 具有循环和功能性人性免疫细胞的小鼠模型（AIM 3）。这将为Kanwar博士提供必要的技能和初步数据，其中这些成像代理和技术在5年K08奖励期间进行了优化，可以将其作为R01赠款应用程序转化为人类受试者。 公共卫生相关性： 以非侵入性的体内方式提高对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在公众身上所承担的医疗负担，因为新型成像方式将扩大我们对IBD的了解，并导致适当的和细胞的特定治疗策略。