Targeting TRAPPC11 as a therapeutic in inherited dilated cardiomyopathy

The National Heart, Lung, and Blood Institute awarded The Leland Stanford Junior University $150,104 on September 30, 2025, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate TRAPPC11 as a therapeutic target for inherited dilated cardiomyopathy.

The funded research will evaluate TRAPPC11 inhibition as a potential treatment for dilated cardiomyopathy caused by TNNT2 mutations and other forms of the disease. The investigator will conduct knockdown studies in a mouse model of TNNT2 dilated cardiomyopathy and in human induced pluripotent stem cell-derived cardiomyocytes. Using CRISPR/CAS9 genome editing, the work will also test the effects of single nucleotide polymorphisms in TRAPPC11 associated with left ventricular hypertrophy on endoplasmic reticulum function in healthy and diseased cell models, assessing their protective potential. The study will establish translational and mechanistic rationale for targeting TRAPPC11 in dilated cardiomyopathy and includes a training program designed to support the investigator's development as an independent researcher.

Performance occurs at Stanford's Palo Alto, California campus. The period of performance runs from September 30, 2025, through August 31, 2028. This is a project grant, classified as assistance funding.

Abstract

Dilated cardiomyopathy (DCM) is a common cause of heart failure with a severe lack of therapeutics, creating a significant clinical burden. The gene TRAPPC11 emerged from a whole transcriptome, functional screen for therapeutic targets for DCM using patient-derived human induced pluripotent stem cell-derived cardiomyocytes (hipsc-CMS), demonstrating reversion of contractile dysfunction upon knockdown in DCM hipsc-CMS. TRAPPC11 is a modulator of endoplasmic reticulum (ER) stress. Since ER stress is recognized as a pathophysiological driver in DCM, my overarching hypothesis is that inhibition of TRAPPC11 would be therapeutic for DCM caused by TNNT2 mutations and possibly more broadly for other forms of DCM. This hypothesis will be tested through knockdown of TRAPPC11 in a mouse model of TNNT2 DCM and in myofilament and nonmyofilament induced DCM in hipsc-CMS. Interestingly, single nucleotide polymorphisms (snps) in TRAPPC11 are associated with left ventricular hypertrophy (LVH) in response to pressure overload in african americans. Therefore, my secondary hypothesis is that common mechanisms underlie TRAPPC11's effect on hypertrophy induction and its therapeutic potential for DCM. Using crispr/CAS9 genome editing, i will test the effects of TRAPPC11 snps associated with LVH on ER/SR function in healthy hipsc-CMS and introduce key snps into DCM hipsc-CMS to assess their protective potential. Completion of this study will establish a translational and mechanistic rationale for targeting TRAPPC11 in DCM, and might warrant monitoring clinical outcomes of people carrying these snps for evidence supporting translatability of targeting TRAPPC11 to treat DCM. The training program proposed in this fellowship application was created to support my potential to become an independent investigator in the future. IT will take place in the highly supportive, rich academic environment of stanford university, where i will have access to state-of-the-art facilities and the opportunity to interact with leading cardiovascular researchers. The plan encompasses scientific technical skills, professional development skills, and both written and oral communication skills and will prepare me for writing my career development award.