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Genetic and mechanistic interrogation of a magnesium transporter with primate-specific function in the cardiac pacemaker and arrhythmias

Award Number: K08HL179452
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Genetic and mechanistic interrogation of a magnesium transporter with primate-specific function in the cardiac pacemaker and arrhythmias - Cardiovascular disease (CVD) is the leading cause of morbidity and mortality. Mice have greatly advanced our understanding of CVD genetics and therapeutics, but major aspects of CVD remain poorly modeled in mice, including cardiac arrhythmias. I helped establish mouse lemurs as a new primate genetic model organism valuable for studying human arrhythmias. In a cardiac screen of several hundred mouse lemurs, I discovered the first cases of mouse lemur CVD, including eight arrhythmias mimicking major human pathologies. Two show familial clustering, including an intermittent bradycardia resembling hereditary human sick sinus syndrome (SSS), which has been mapped to the pacemaker channel HCN4 and the cardiac sodium channel SCN5A. I performed the first genetic mapping in mouse lemur, and mapped lemur SSS to SLC41A2, a little studied magnesium transporter. Although mouse SLC41A2 knockouts do not show a cardiac pacemaker phenotype, CRISPR KO of SLC41A2 in human iPSC-derived cardiac pacemaker cells slowed their calcium transient firing rate. Functional imaging revealed rhythmic, oscillatory Mg2+ activity in control pacemaker cells – the first evidence that magnesium cycles intrinsically within the pacemaker. This rhythmicity was disrupted in SLC41A2 KO cells, suggesting a novel magnesium-regulated mechanism of cardiac pacemaking. The results indicate that SLC41A2 is the lemur SSS disease gene, SLC41A2 plays a critical role in regulating cardiac pacemaker rate (automaticity), and this role is intrinsic to the cardiac pacemaker cells and primate-specific. Although magnesium therapy is used clinically to treat human cardiac tachyarrhythmias, there is no known intrinsic role of magnesium in pacemaker function. This proposal tests the hypothesis that the intracellular distribution of magnesium is dynamically regulated by SLC41A2 in human pacemaker cells, and transient elevation in magnesium modulates the transient cytosolic calcium spikes known to initiate each pacemaker cycle. The specific aims are: (1) To determine the role of SLC41A2 magnesium transporter in regulating human cardiac pacemaker activity. (2) To determine if SLC41A2 is a causative gene of human sick sinus syndrome (SSS) in idiopathic cases of familial SSS. (3) To identify primate-specific genes and cell types of the cardiac conduction system (CCS) by generating a 3D mouse lemur CCS transcriptomic cell atlas and comparing the results to human and mouse. This work will characterize a critical new component of the human cardiac pacemaker and test a novel model of pacemaker automaticity with an important, dynamic role for magnesium. It identifies a potential new cause of human sick sinus syndrome, and a route to new arrhythmia diagnostics and therapeutics. It exploits a new tractable, primate genetic model organism for arrhythmia research, generalizable to other arrhythmias, cardiovascular diseases, and tissues. This project also provides a platform to develop a multidisciplinary physician-scientist to lead, innovate, and clinically integrate cutting-edge advances in cardiac genetics.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $165,888 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	1	7/23/2026	NEW	$165,888
														Subtotal = $165,888

Grand Total All Awards = $165,888

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Genetic and mechanistic interrogation of a magnesium transporter with primate-specific function in the cardiac pacemaker and arrhythmias

Award Number: K08HL179452

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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