Mechanisms of sarcomere functional remodeling in the postprandial python heart

Active Project Grant Awarded Last action

Award ID
F31HL184667
Recipient
Awarding agency
Obligated
$87,054

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 0% complete
Originally
Place of performance
Boulder, CO 80303, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Common pathological signatures of heart failure include decreased contractility and increased stiffness, leading to decreased cardiac output. Identifying the underlying molecular mechanisms behind these phenotypes is critical for targeted therapeutic development to address heart disease. Pythons represent a unique model organism to study cardiac hypertrophy and altered cardiac function. After feeding, pythons undergo rapid physiological cardiac hypertrophy within 72 hours, followed by subsequent regression. Recent work from our lab also showed that pythons rapidly increase cardiac myofibril active tension and decrease myofibril passive tension after feeding. Identifying the regulatory mechanisms that promote rapid tension changes in the post-FED python heart may allow for the discovery of novel, conserved mechanistic targets for modifying cardiac function in humans. We conducted a preliminary global phospho-proteomics study with samples from fasted and FED ball python ventricles. I identified 19 differentially phosphorylated resides on cardiac myosin heavy chain (a key determinant of active tension/force) and 133 differentially phosphorylated sites on titin (a key determinant of passive tension). The majority of these sites are conserved in humans and reside within known myosin and titin functional domains. We have also generated biochemical data suggesting that ATP turnover of myosin is altered after feeding. The goals of this work are to further our mechanistic understanding of how phosphorylation of specific residues regulates titin stiffness and be the first study to assess how phosphorylation in the motor domain and proximal rod region affects myosin heavy chain function. Specifically, I will conduct single molecule atomic force microscopy (with the perkins lab at CU boulder) and thermodynamic stability assays to determine how phospho-mimetic mutations affect the elastic and thermodynamic properties of titin. I will also use phospho-null/mimetic mutations within the motor and proximal rod regions of cardiac myosin heavy chain to mimic changes that occur after feeding and characterize the impact on myosin function and structural states with biochemical and electron microscopy assays. My long- term goals are to identify how pythons rapidly tune cardiac function and undergo hypertrophy in a physiological fashion (specifically through alternative splicing and post-translational modifications), and how this compares with mammalian models of physiological and pathological remodeling. This fellowship will allow me to learn single molecule force microscopy techniques from world-leading experts, gain expertise with myosin functional assays that our lab has significant experience in, and improve my background in muscle biophysics. These skills will help prepare me for a future career as an independent investigator in the field of cardiac remodeling.

Transactions

Action Obligated Date
Amendment $43,527
Amendment $0
Original award $43,527

Quick answers

Who received award F31HL184667?

F31HL184667 was awarded to The Regents Of The University Of Colorado by National Heart Lung and Blood Institute (National Institutes of Health) on December 1, 2026.

How much is award F31HL184667 worth?

$87,054 has been obligated on F31HL184667.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login