SOCS proteins as inhibitors of immune surveillance in the melanoma microenvironme

SOCS 蛋白作为黑色素瘤微环境中免疫监视的抑制剂

基本信息

批准号：
7683943
负责人：
Gregory B. Lesinski
金额：
$ 15.1万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7683943
关键词：
Activated Lymphocyte Applications Grants Area Autoimmune Process Basic Science Biological Markers Biopsy CD8B1 gene Cancer Control Cancer Patient Cells Clinical Clinical Oncology Clinical Research Clinical Trials Collaborations Commit Comprehensive Cancer Center Continuing Education Cytokine Inducible SH2-Containing Protein Data Development Development Plans Diagnosis Diagnostic Neoplasm Staging Disease Doctor of Philosophy Educational workshop Effector Cell Environment Epigenetic Process Family Funding Future Genomics Goals Human Immune Immune response Immune system Immunologic Monitoring Immunologic Surveillance Immunology Immunosuppressive Agents In Situ Incidence Institution Integration Host Factors Interferons Interleukin-10 Interleukin-2 Interleukin-6 Investigation K22 Award Laboratories Lead Location Malignant Neoplasms Master of Public Health Mediating Mediator of activation protein Medical Genetics Mentors Metastatic Melanoma Methods Modeling Molecular Molecular Virology Morbidity - disease rate Mus Nature Neoplasm Metastasis Ohio Patients Play Population Process Proteins Public Health Research Research Personnel Role Sampling Shapes Signal Transduction Signaling Protein Skin Cancer Stromal Cells T-Lymphocyte T-Lymphocyte and Natural Killer Cell Testing Therapeutic Thick Time Training Translating Translational Research United States Universities Up-Regulation Vitiligo Work age group anticancer research autocrine career development clinically relevant cytokine design experience immune function immunogenic immunogenicity immunosuppressive substance infancy inhibitor/antagonist insight lymph nodes meetings melanoma mortality neoplastic cell novel novel strategies oncology paracrine patient oriented population based prevent professor programs protein expression research study response skills theories tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): This proposal is meant to assist Dr. Lesinski in his transition to becoming an independent investigator in human cancer research. Dr. Lesinski joined the Department of Molecular Virology, Immunology and Medical Genetics at The Ohio State University as an Assistant Professor on the Research Track in 2005. This three year proposal consists of a Career Development Plan designed to further enhance his ability to conduct cancer research in collaboration with clinicians. Dr. Lesinski will continue his education through involvement in various educational seminars, workshops and participation in national scientific meetings. Importantly, he will gain extensive training in the responsible conduct of clinical research, and will complete the didactic requirements to obtain a formal Master of Public Health in Clinical Investigation. Included in this proposal is a Research Plan that extends Dr. Lesinski's prior experience in immunology and oncology into novel studies that investigate how the immune system can mediate cancer control in the setting of malignant melanoma. Specifically, Dr. Lesinski will study how immunosuppressive cytokines act to inhibit the ability of immune cells to control the development of melanoma. It has previously been established that a separate group of immunostimulatory cytokines (e.g., the interferons) are critical for cancer immunosurveillance by host immune cells. The action of interferons can be negatively regulated by a group of proteins termed the "Suppressors of Cytokine Signaling" or SOCS proteins. It is hypothesized that cytokines present in the tumor microenvironment function by upregulating SOCS proteins within immune cells, making them less responsive to the cytokines that mediate immunosurveillance. Dr. Lesinski will utilize lymph node biopsies from melanoma patients to determine whether the immunosuppressive cytokines present in the tumor microenvironment lead to increased expression of SOCS proteins within immune cells, and inhibit their ability to control the development of malignant melanoma. This research is novel because it will allow for new strategies to harness the full potential of the immune system against early-stage cancer. Thus, effectively turning the immune system against micrometastatic disease is relevant to public health because it represents a promising means of reducing cancer incidence, mortality and morbidity. The data obtained from these initial studies will be used to prepare an R01 grant application focused on mechanisms of immune-mediated cancer control within two years of the K22 award. The Ohio State University's NCI designated Comprehensive Cancer Center (OSU CCC) provides the ideal location for this training. The institution is committed towards the development of Dr. Lesinski, and fully supports his decision to devote 75% of his time towards this goal.

描述（由申请人提供）：该提案旨在帮助Lesinski博士过渡到成为人类癌症研究的独立研究者。 Lesinski博士在俄亥俄州立大学加入了分子病毒，免疫学和医学遗传学系，在2005年担任研究轨道的助理教授。该三年提案包括一项职业发展计划，旨在进一步增强其与临床医生合作进行癌症研究的能力。 Lesinski博士将通过参与各种教育研讨会，讲习班和参加国家科学会议，继续他的教育。重要的是，他将在负责任的临床研究中获得广泛的培训，并完成教义要求，以获得正式的公共卫生临床研究硕士。该提案中包括一项研究计划，该计划将Lesinski博士的先前免疫学和肿瘤学经验扩展到新的研究中，研究免疫系统如何在恶性黑色素瘤的情况下介导癌症的控制。具体而言，Lesinski博士将研究免疫抑制性细胞因子如何作用以抑制免疫细胞控制黑色素瘤发育的能力。以前已经确定，一组单独的免疫刺激细胞因子（例如，干扰素）对于宿主免疫细胞的癌症免疫监视至关重要。干扰素的作用可能会受到一组称为“细胞因子信号抑制剂”或SOCS蛋白质的蛋白质的负调节。假设肿瘤微环境功能中存在的细胞因子通过上调免疫细胞中的SOCS蛋白，从而使它们对介导免疫监视的细胞因子的反应较低。 Lesinski博士将利用来自黑色素瘤患者的淋巴结活检来确定肿瘤微环境中存在的免疫抑制性细胞因子是否导致免疫细胞中SOCS蛋白的表达增加，并抑制其控制恶性黑色素瘤发育的能力。这项研究是新颖的，因为它将允许新的策略利用免疫系统的全部潜力，以防止早期癌症。因此，有效地将免疫系统针对微转移性疾病进行了与公共卫生有关，因为它代表了降低癌症发病率，死亡率和发病率的有希望的手段。从这些初步研究中获得的数据将用于准备R01赠款应用程序，该授予申请专注于K22颁发后两年内免疫介导的癌症控制机制。俄亥俄州立大学的NCI指定综合癌症中心（OSU CCC）为这项培训提供了理想的位置。该机构致力于开发Lesinski博士，并充分支持他将75％的时间朝着这一目标迈进的决定。