The Structural Basis of TAM Receptor Oligomerizarion and Co-receptor Interactions

项目摘要/摘要 受体是一个临床上重要且机制研究较少的RTK亚家族。这些受体有 在维持细胞动态平衡中的重要作用，通过清除凋亡细胞和控制 炎症和免疫反应。联系到他们重要的监管角色，的监管失调 受体与多种疾病状态有关，包括心血管疾病、遗传性失明、 不孕不育、自身免疫性疾病、慢性炎症和癌症。此外，受体介导 信号通路可以被病毒劫持以进入宿主细胞。虽然人们对……的兴趣越来越大 受体作为治疗靶点，其在体内平衡过程中的多重作用为 制定治疗策略。了解受体的激活机制对进一步研究 研究靶向治疗的潜在发展。虽然人们普遍认为这些受体 为了通过经典的受体诱导的二聚化来激活，我的初步工作提出了第一个深入的 生物化学的研究表明，这种简化的观点可能不适用于受体。 重要的是，为了充分理解TAM是如何被激活的，我打算利用结构、 生物物理和生化方法研究的寡聚和与其他受体的串扰。 这些研究将指导受体激活的知情理论的发展，并提供 可用于开发癌症和病毒的新疗法的重要见解 自身免疫性疾病。耶鲁大学癌症生物研究所的凯瑟琳·弗格森博士的实验室提供了一个 支持和创新的研究环境，以进行这项研究，以及旨在 在提高向独立过渡所需的技能方面。有机会获得丰富的资源和 在这项申请中建议的方法方面的领先专家，我将获得额外的高级培训 显微镜技术，以加强我之前和正在进行的培训。专业训练与专业训练相结合 在其他结构和生物物理方法方面，由我领导的导师和职业发展活动 导师和耶鲁大学，参与UE5活动，以及我在多样性，公平办公室的持续工作 以及耶鲁大学的参与，将为我领导一个强大的独立研究项目做好准备。

PROJECT SUMMARY/ABSTRACT TAM receptors are a clinically important and mechanistically under-studied RTK subfamily. These receptors have a vital role in maintaining cellular homeostasis through the clearance of apoptotic cells and control of inflammatory and immune responses. Linked to their important regulatory roles, dysregulation of TAM receptors is implicated in numerous disease states including cardiovascular disease, hereditary blindness, infertility, autoimmune disorders, chronic inflammation and cancer. In addition, TAM receptor mediated signaling pathways can be hijacked by viruses to gain entry into host cells. While there is growing interest in TAM receptors as therapeutic targets, their multiple roles in homeostatic processes create challenges for developing therapeutic strategies. Understanding TAM receptor activation mechanisms is important for further investigation of the potential development of targeted therapies. While these receptors are commonly believed to be activated through classical receptor-induced dimerization, my preliminary work presents the first in-depth study of the biochemistry and suggests that this simplified view may not be applicable to TAM receptors. Importantly, to fully understand how TAMs are activated, I intend to utilize a combination of structural, biophysical and biochemical approaches to investigate TAM oligomerization and cross-talk with other receptors. These studies will guide the development of informed theories of TAM receptor activation and provide important insights that may be used for the development of new therapeutics in cancer and viral and autoimmune diseases. The laboratory of Dr. Kathryn Ferguson at the Yale Cancer Biology Institute provides a supportive and innovative research environment to conduct this research, as well as mentorship that is aimed at improving skills necessary for a transition to independence. With access to a wealth of resources and to leading experts in the approaches proposed in this application, I will gain additional training in advanced microscopy techniques to augment my previous and ongoing training. The combination of specialized training in additional structural and biophysical approaches, mentorship and career development activities led by my mentors and at Yale, participation in UE5 activities and my continued work with the Office of Diversity, Equity and Inclusion at Yale, will prepare me to lead a strong independent research program.