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

TAM 受体寡聚和共受体相互作用的结构基础

• 批准号: 10759499
• 负责人: Chrystal Starbird
• 金额: $ 24.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759499
• 关键词: Adult; Affect; Apoptotic; Autoimmune Diseases; Binding; Biochemical; Biochemistry; Biological Process; Biophysics; Cancer Biology; Cardiovascular Diseases; Cell Surface Receptors; Cell Survival; Cell membrane; Cells; Chronic; Clinical; Complex; Cytokine Receptors; Data; Development; Dimerization; Disease; Environment; Epidermal Growth Factor Receptor; Extracellular Domain; Family; Fibronectins; Homeostasis; Immune response; Immune system; Infertility; Inflammation; Inflammatory Response; Investigation; Kinetics; Laboratories; Length; Ligand Binding; Ligands; Link; Maintenance; Malignant Neoplasms; Mediating; Membrane; Mentors; Mentorship; Microscopy; Modeling; Molecular; Molecular Conformation; Nature; Phosphorylation; Phosphotransferases; Play; Process; Proliferating; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Research; Resources; Role; Signal Pathway; Signal Transduction; Structure; Techniques; Testing; Therapeutic; Tissues; Training; Vascular System; Virus; Virus Diseases; Work; biophysical analysis; biophysical techniques; career development; cell motility; dimer; equity, diversity, and inclusion; extracellular; hereditary blindness; improved; innovation; insight; interest; novel therapeutics; programs; receptor; receptor-mediated signaling; response; skills; targeted treatment; theories; therapeutic target

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.

项目摘要/摘要 TAM受体是临床上重要的并且在机制上研究不足的RTK亚家族。这些受体具有 在通过清除凋亡细胞和控制细胞凋亡来维持细胞内稳态中起重要作用。 炎症和免疫反应。与其重要的调节作用有关，TAM的调节异常 受体与许多疾病状态有关，包括心血管疾病，遗传性失明， 不孕症、自身免疫性疾病、慢性炎症和癌症。此外，TAM受体介导的 信号通路可被病毒劫持以进入宿主细胞。虽然人们越来越关注 TAM受体作为治疗靶点，它们在体内平衡过程中的多重作用给治疗带来了挑战。 制定治疗策略。了解TAM受体激活机制对于进一步研究TAM受体的功能非常重要。 研究靶向治疗的潜在发展。虽然这些受体通常被认为 通过经典的受体诱导的二聚化被激活，我的初步工作提出了第一个深入的 生物化学的研究，并建议这种简化的观点可能不适用于TAM受体。 重要的是，为了充分了解TAM是如何被激活的，我打算利用结构， 生物物理和生物化学方法来研究TAM寡聚化和与其他受体的串扰。 这些研究将指导TAM受体激活的知情理论的发展，并提供 重要的见解，可用于开发新的治疗癌症和病毒， 自身免疫性疾病耶鲁大学癌症生物学研究所的凯瑟琳·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，以及指导，目的是 提高向独立过渡所需的技能。拥有丰富的资源， 在此应用程序中提出的方法的领先专家，我将获得先进的额外培训 显微镜技术，以加强我以前和正在进行的培训。专业培训相结合 在其他结构和生物物理方法中，由我领导的导师和职业发展活动 导师和耶鲁大学，参与UE 5活动，并继续与多样性，公平办公室合作 和包容在耶鲁大学，将准备我领导一个强大的独立研究计划。