SOCS proteins as inhibitors of immune surveillance in the melanoma microenvironme

描述（由申请人提供）：本提案旨在帮助Lesinski博士过渡到成为人类癌症研究的独立研究者。2005年，莱辛斯基博士加入俄亥俄州立大学分子病毒学、免疫学和医学遗传学系，担任研究方向的助理教授。这项为期三年的计划包括一个职业发展计划，旨在进一步提高他与临床医生合作进行癌症研究的能力。莱辛斯基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来继续他的教育。重要的是，他将在负责任的临床研究行为方面获得广泛的培训，并将完成获得正式的临床研究公共卫生硕士学位的教学要求。该提案包括一项研究计划，该计划将Lesinski博士在免疫学和肿瘤学方面的先前经验扩展到研究免疫系统如何在恶性黑色素瘤的背景下介导癌症控制的新研究中。具体来说，莱辛斯基博士将研究免疫抑制细胞因子如何抑制免疫细胞控制黑色素瘤发展的能力。先前已经确定，一组单独的免疫刺激细胞因子（如干扰素）对宿主免疫细胞的癌症免疫监视至关重要。干扰素的作用可被一组称为“细胞因子信号抑制因子”或SOCS蛋白的蛋白质负向调节。据推测，存在于肿瘤微环境中的细胞因子通过上调免疫细胞内的SOCS蛋白发挥功能，使其对介导免疫监视的细胞因子的反应减弱。Lesinski博士将利用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展的能力。这项研究是新颖的，因为它将允许利用免疫系统的全部潜力来对抗早期癌症的新策略。因此，有效地使免疫系统对抗微转移性疾病与公共卫生相关，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拨款申请，重点是免疫介导的癌症控制机制，在K22奖后的两年内。俄亥俄州立大学NCI指定的综合癌症中心（OSU CCC）为这项培训提供了理想的场所。该机构致力于莱辛斯基博士的发展，并完全支持他将75%的时间用于这一目标的决定。

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.