SOCS proteins as inhibitors of immune surveillance in the melanoma microenvironme

描述(申请人提供)：本提案旨在帮助莱辛斯基博士转变为人类癌症研究领域的独立研究员。莱辛斯基博士于2005年加入俄亥俄州立大学分子病毒学、免疫学和医学遗传学系，担任研究轨道助理教授。这项为期三年的提案包括职业发展计划，旨在进一步增强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加各种教育研讨会、研讨会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方面获得广泛的培训，并将完成教学要求，以获得正式的临床调查公共卫生硕士学位。这项建议包括一项研究计划，该计划将莱辛斯基博士在免疫学和肿瘤学方面的先前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背景下调节癌症控制。具体而言，莱辛斯基博士将研究免疫抑制细胞因子如何作用于抑制免疫细胞控制黑色素瘤发展的能力。以前已经证实，一组单独的免疫刺激细胞因子(如干扰素)对宿主免疫细胞对癌症的免疫监视至关重要。干扰素的作用可以被一组被称为“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，肿瘤微环境中存在的细胞因子通过上调免疫细胞内的SOCS蛋白来发挥作用，使它们对介导免疫监视的细胞因子反应较差。Lesinski博士将利用黑色素瘤患者的淋巴活检来确定肿瘤微环境中存在的免疫抑制细胞因子是否会导致免疫细胞内SOCS蛋白表达增加，并抑制它们控制恶性黑色素瘤发展的能力。这项研究是新颖的，因为它将允许新的策略来利用免疫系统的全部潜力来对抗早期癌症。因此，有效地使免疫系统对抗微转移疾病与公共健康相关，因为它是降低癌症发病率、死亡率和发病率的一种有前途的手段。从这些初步研究中获得的数据将用于准备一份R01拨款申请，重点是在K22获奖后的两年内研究免疫介导的癌症控制机制。俄亥俄州立大学的NCI指定的综合癌症中心(OSU CCC)为这次培训提供了理想的地点。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.