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.

项目总结/文摘