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: 10349217
• 负责人: Chrystal Starbird
• 金额: $ 9.67万
• 依托单位: YALE UNIVERSITY
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349217
• 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; Institutes; Investigation; Kinetics; Laboratories; Lead; Length; Ligand Binding; Ligands; Link; Maintenance; Malignant Neoplasms; Mediating; Membrane; Mentors; Mentorship; Microscopy; Modeling; Molecular; Molecular Conformation; Nature; Phosphorylation; Phosphotransferases; Play; Process; 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; diversity and equity; 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，机械学的RTK亚科。这些受体有 通过凋亡细胞的清除和控制 炎症和免疫反应。与他们重要的调节作用有关，TAM的失调 受体与许多疾病状态有关，包括心血管疾病，遗传失明， 不育，自身免疫性疾病，慢性炎症和癌症。另外，TAM受体介导 信号通路可以被病毒劫持，以进入宿主细胞。虽然对 TAM受体作为治疗靶标，它们在体内稳态过程中的多重角色为 制定治疗策略。了解TAM受体激活机制对于进一步 研究目标疗法的潜在发展。虽然通常相信这些受体 要通过经典受体诱导的二聚化激活，我的初步工作是第一个深入的 对生物化学的研究，并建议这种简化的观点可能不适用于TAM受体。 重要的是，要充分了解TAM的激活方式，我打算利用结构性的组合 生物物理和生化方法研究TAM寡聚化并与其他受体进行串扰。 这些研究将指导TAM受体激活的知情理论的发展，并提供 可能用于开发癌症和病毒疗法新疗法的重要见解 自身免疫性疾病。耶鲁癌症生物学研究所的凯瑟琳·弗格森博士的实验室提供了 支持和创新的研究环境，以进行这项研究以及针对的指导 提高过渡到独立所必需的技能。获取大量资源并 在本申请中提出的方法中的领先专家，我将获得高级培训 显微镜技术，以增强我以前的培训和正在进行的培训。专业培训的结合 在我的其他结构和生物物理方法中，我的指导和职业发展活动由我 导师和耶鲁大学，参加UE5活动，以及我在多元化办公室的持续工作 并在耶鲁大学加入将为我领导强大的独立研究计划做好准备。