The long term objective of this Project is to understand how mutations in a general chaperone, a-B crystallin(CryAB) can affect global cardiac function during stress response signaling. The short term goal is to definethe toxic mechanism of a mutant CryAB that causes the cardiovascular disease, Desmin-RelatedCardiomyopathy (DRM), which is characterized by the appearance of electron-dense, proteinaceousaggregates in the sarcoplasm. We noted that, internal in the cardiomyocytes is a protein that reacts to anantibody detecting a toxic pre-amyloid oligomer (PAO), which is normally associated with the amyloid-basedneurodegenerative diseases. Subsequently, we found that PAO is widespread in cardiomyocytes derivedfrom human heart failure patients of different etiologies, implying that PAO may be an important mediator ofcardiovascular disease. We think that the CryAB mutant mouse is a uniquely useful and relevant system thatmodels a heretofore understudied phenomenon, accumulation of PAO, which is surprisingly widespread inboth adult and pediatric heart failure. The goal, therefore, is to understand the pathogenic pathway thatresults in PAO accumulation, determine its toxicity in cardiomyocytes and define potential therapeutic targetsor modalities for DCM and heart failure that occurs as a result of CryABR120G expression.
Aim 1 will test thehypothesis that cardiomyocyte accumulation of pre-amyloid oligomer (PAO) is toxic and can directly causeheart failure. We will create a series of transgenic mice in which inducible PAO-genic protein expression isrestricted to the cardiomyocytes and measure the cytotoxicity of expression as well as the pathogenicsequelae.
Aim 2 will use inducible, cardiomyocyte-specific CryABR120G expression to test if PAO-mediatedheart failure can be reversed.
Aim 3 will express anti-apoptotic factors in CryABR120G DRM to determine ifprevention of programmed cell death can, in the face of continuous CryABR120G expression, prevent heartfailure or even reverse existing disease. We hypothesize that despite the occurrence of cardiomyocyteapoptosis in CryABR120G hearts, programmed cell death is peripheral and collateral to the primary etiologythat transits the hearts toward failure in this model. These studies have the potential of establishing broadlinkages between the neurodegenerative and cardiovascular diseases and identifying new targets forinterfering with processes that occur in a broad range of cardiovascular disease.
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