Characterization Of A Novel Family Of LIM-only Proteins; Role In Skeletal Muscle Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$423,564.00
Summary
This project aims to study the role of a new family of related proteins in skeletal muscle. One of these proteins has been shown to be deficient in muscle cancers. These proteins are important for the development and normal functioning of muscle. Related proteins have been shown to be linked with heart failure in animals. These proteins also potentially interact with proteins causing muscular dystrophy. We have identified a new family of proteins in skeletal muscle. These proteins contain so-cal ....This project aims to study the role of a new family of related proteins in skeletal muscle. One of these proteins has been shown to be deficient in muscle cancers. These proteins are important for the development and normal functioning of muscle. Related proteins have been shown to be linked with heart failure in animals. These proteins also potentially interact with proteins causing muscular dystrophy. We have identified a new family of proteins in skeletal muscle. These proteins contain so-called LIM domains, which mediate binding to other proteins. This study proposes to determine how these proteins influence skeletal muscle development and the consequences of abnormal levels of these proteins. This may lead to insights into the mechanism of cardiac failure, muscle cancers and muscular dystrophy.Read moreRead less
Structure-function Analysis Of Nuclear Receptor And Cofactor Action: Evidence For A Role In Muscle.
Funder
National Health and Medical Research Council
Funding Amount
$692,040.00
Summary
Hormone receptors have critical roles in almost all aspects of physiology by transducing the effects of hormones into metabolic responses. There are ~45 orphan hormone receptors encoded by distinct genes in humans, since all receptors are important in the treatment of human disease, the plethora of orphan receptors has been the catalyst for the development of a new paradigm, reverse endocrinology. Reverse endocrinology is the process whereby the orphan hormone receptor is used to search for a pr ....Hormone receptors have critical roles in almost all aspects of physiology by transducing the effects of hormones into metabolic responses. There are ~45 orphan hormone receptors encoded by distinct genes in humans, since all receptors are important in the treatment of human disease, the plethora of orphan receptors has been the catalyst for the development of a new paradigm, reverse endocrinology. Reverse endocrinology is the process whereby the orphan hormone receptor is used to search for a previously unknown hormone, and metabolic pathway. We are interested in the orphan hormone receptors, Rev-erbA and RVR, orphan members of the receptor superfamily. Rev-erb alpha expression is regulated by fibrates, widely used hypolipidemic drugs, and the circadian cycle. Rev-erbs mediate the regulation of lipid metabolism and peroxisomal beta oxidation. Furthermore, Rev-erbs are acutely induced during brain seizures, postulated to regulate cerebellar plasticity, and involved in growth control. In view of these critical regulatory roles, and the success of reverse endocrinology to date, we intend to complete the structural analysis of the Rev-erb and RVR as a tool to identify the hormone that binds this receptor. Hormone receptors recruit proteins called nuclear receptor cofactors, that function as regulators of gene expression. The cofactors regulate gene expression and development. Furthermore these cofactors, when misregulated result in the onset of disease and carcinogenesis, which underscores the need for achieving a high resolution view of their function in many tissues. Along these lines, we are interested in exmining the function of these cofactors in muscle. Understanding the molecular role of the NR cofactors during muscle differentiation will be a critical step toward elucidating the dysregulation-function of these proteins in muscle diseases, such as rhabdomyosarcoma and inflammatory myopathy that have cofactor deficiency.Read moreRead less