• Home
  •  > Grant Detail
  • By Concept
  • By Last Name
  • By Full Text

 

Grant Detail

The grant detail shows the name of the PI, active dates of the project, the funding institute and the abstract of the grant. This abstract is what is used to create the fingerprint of the grant. If any publications referencing this grant are found in the data, they will be listed here as well.



Obscurin & Myofibrils in Cardiac & Skeletal Muscle

Robert J Bloch

1 June 1999 - 30 June 2009
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

Abstract

In recent years, we have learned a great deal about the assembly of thick and thin filaments in striated muscle, and about the proteins that regulate the release and re-uptake of Ca2+ essential for the contractile cycle. We know much less, however, about the mechanisms that integrate thick and thin filaments into myofibrils, and about the proteins that organize the sarcoplasmic reticulum (SR) and transverse (t-) tubules so regularly around sarcomere. The recent discovery of obscurin offers new ways to address these questions. Obscurin is an approximately 800 kDa protein with structural homology to titin. It is the only protein of the titin superfamily that is concentrated, at least in part, at the periphery of sarcomeres, primarily around M-lines and Z-disks. Obscurin is composed largely of tandem Ig domains but also has signaling domains and, at its extreme COOH-terminus, a binding site for a small, integral membrane form of ankyrin 1 that is concentrated in the network SR. Given its apparent ability to concentrate at the periphery of the myofibril around M-lines and Z-disks and its high affinity for an integral protein of the SR membrane, obscurin is ideally suited to play key roles in assembling and organizing both the sarcomere and the SR. We propose to test this general hypothesis through 4 specific aims: (1) to learn how obscurin is organized with respect to key structures within sarcomeres; (2) to learn how obscurin binds to elements in the contractile apparatus; (3) to assess the effect on morphogenesis of the myofibrils and associated membranes of altering the activity of obscurin with siRNA and thru adenoviral overexpression of particular binding domains; and (4) to investigate the role of obscurin's binding to small ankyrin 1 in the assembly, organization and function of the SR. Mutations in proteins of the contractile apparatus, including some that affect the assembly or stability of contractile elements, have been implicated in hypertrophic cardiomyopathies and muscular dystrophies. The results of our experiments should reveal some of the key mechanisms involved in assembling contractile proteins into sarcomeres and in determining their association with the SR.

18 Resulting Publications

Scientific Context

This section shows information that has been computed by using the fingerprint of the grant, including related publications, related experts and related grants - all with fingerprints representing significant amounts of overlap between their fingerprint and this grant. The red dots indicate whether those experts or terms actually appear within this grant, showing potential and actual connections.

Related Grants

Related Publications