Mechanisms of Tyrosine Kinase Inhibitor-induced Sinoatrial Node Dysfunction
About This Grant
PROJECT SUMMARY Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), especially Anaplastic Lymphoma Kinase (ALK) inhibitors (ALKi), which have significantly improved progression-free survival in ALK-positive NSCLC patients. Despite these advances, ALKi treatment is associated with adverse cardiac effects, such as bradycardia and sinoatrial node (SAN) dysfunction (SAND), which pose serious risks, including sudden cardiac death. These adverse effects necessitate thorough evaluation of ALKi- induced cardiotoxicity to enhance patient safety and treatment efficacy. This K99/R00 proposal details a five-year research plan designed to uncover the molecular mechanisms of ALKi- induced SAND and to explore therapeutic interventions. The project leverages human induced pluripotent stem cell-derived sinoatrial node-like cells (iSANCs), engineered heart tissues (EHTs), and advanced single-cell omics techniques. Dr. Ren will test the hypothesis that ALKi induces SAND by disrupting Ca2+ and membrane clocks through off-target effects on other kinases and that SAN-specific restoration of disrupted protein kinase may counteract ALKi-SAND. In Aim 1 (K99), Dr. Ren will establish an in vitro model to recapitulate the clinical phenotype of ALKi-SAND at the single-cell level using iSANC. Single-cell RNA sequencing will then be performed on pooled iSANCs to uncover transcriptomic dysregulation associated with ALKi-induced SAND. In Aim 2 (K99), Dr. Ren will assess ALKi-induced electrical remodeling and identify impacts on SAN automaticity by investigating the effects on calcium and membrane clocks as well as exploring protein kinase’s potential to rescue observed phenotypes. In Aim 3 (R00), Dr. Ren will evaluate the therapeutic potential in ALKi-SAND in a more physiologically relevant settings with pacemaker EHTs and a mouse model. With the well-structured research training plan during the K99 phase, the support from esteemed mentors, advisors, and collaborators, as well as the outstanding environment at Stanford University, Dr. Ren will be equipped with advanced knowledge in stem cell biology, cardio-oncology, and bioengineering. The development of iPSC-derived pacemaker disease modeling and a population-scale platform for evaluating the impact of cancer drugs on the SAN (K99), as well as mechanistic insights and therapeutic strategies for TKI-induced SAN dysfunction (K99/R00), will enable Dr. Ren to conduct disease modeling and translational research specifically in cardio-oncology and cardiac pacemaker research. The new skills and experience gained during this K99/R00 career development award, combined with Dr. Ren’s prior expertise in cardiac electrophysiology and pacemaker biology, will facilitate Dr. Ren’s transition to an independent career conducting basic and translational research in cardio-oncology.
Grant Summary
Mechanisms of Tyrosine Kinase Inhibitor-induced Sinoatrial Node Dysfunction is a NHLBI - National Heart Lung and Blood Institute grant providing up to $153K for university, nonprofit, healthcare org. Applications are due 2028-05-31 (open). Check eligibility and apply with FindGrants.
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Up to $153K
2028-05-31
- 1Confirm your organization is eligible for Mechanisms of Tyrosine Kinase Inhibitor-induced Sinoatrial Node Dysfunction from NHLBI - National Heart Lung and Blood Institute, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NHLBI - National Heart Lung and Blood Institute before the deadline.
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Mechanisms of Tyrosine Kinase Inhibitor-induced Sinoatrial Node Dysfunction: Frequently Asked Questions
Who is eligible for the Mechanisms of Tyrosine Kinase Inhibitor-induced Sinoatrial Node Dysfunction?
Mechanisms of Tyrosine Kinase Inhibitor-induced Sinoatrial Node Dysfunction is offered by NHLBI - National Heart Lung and Blood Institute and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Mechanisms of Tyrosine Kinase Inhibitor-induced Sinoatrial Node Dysfunction provide?
Mechanisms of Tyrosine Kinase Inhibitor-induced Sinoatrial Node Dysfunction provides up to $153K per award from NHLBI - National Heart Lung and Blood Institute. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Mechanisms of Tyrosine Kinase Inhibitor-induced Sinoatrial Node Dysfunction deadline?
Applications for Mechanisms of Tyrosine Kinase Inhibitor-induced Sinoatrial Node Dysfunction are due 2028-05-31 (open). Because deadlines can change, verify the date with the funder, NHLBI - National Heart Lung and Blood Institute, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Mechanisms of Tyrosine Kinase Inhibitor-induced Sinoatrial Node Dysfunction?
To apply for Mechanisms of Tyrosine Kinase Inhibitor-induced Sinoatrial Node Dysfunction, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NHLBI - National Heart Lung and Blood Institute.