Overview: Visual information is conveyed from the eye to the brain via the optic nerve which contains the axons of the retinal ganglion cells (RGCs). Damage to RGCs and the optic nerve causes permanent vision loss, for example in glaucoma, ischemic optic neuropathies, and traumatic injury. Notably, glaucoma is expected to affect ~80 million people worldwide by 2020, of whom ~10% are predicted to go blind. There are currently no approved medicines or therapies to restore vision after RGC and optic nerve damage, as unlike axons in the peripheral nervous system, RGC axons in the adult mammal do not spontaneously regenerate when damaged. In addition, damage to the optic nerve can result in retrograde degeneration and apoptotic death of the associated RGCs. We are studying the basic cell biology of the RGC in order to discover signaling pathways that regulate RGC survival and optic nerve healing and regeneration in disease. We expect to derive novel insights into RGC biology and develop novel therapeutics to prevent loss of or restore vision. RGCs are central nervous system neurons and share cellular mechanisms with neurons in the brain. Our research should have relevance not just in the field of ophthalmology, but to neurology in general. For example, axon regeneration is a critical issue in human stroke which often involves the white matter.
Overview: Left ventricular hypertrophy is a major risk factor for the development of heart failure, a syndrome of great public heath significance, contributing to 300,000 deaths each year in the U.S. alone. At the cellular level, myocyte hypertrophy is the primary response of the heart to chronic stress. In disease, this non-mitotic growth is accompanied by changes in gene expression, ion fluxes and metabolism that can affect cardiac contractility and induce myocyte apoptosis and interstitial myocardial fibrosis. This pathologic remodeling is the proximate cause of heart failure and the associated morbidity and mortality. Basic questions being asked in the Kapiloff lab include how pathological concentric and eccentric hypertrophy are differentially regulated and whether myocyte hypertrophy can be regulated independently of interstitial fibrosis in disease. We are interested in identifying signaling molecules that might be therapeutically targeted to prevent the pathological cardiac hypertrophy that leads to heart failure.
Cardiac hypertrophy at the whole-organ level reflects non- mitotic growth of the cardiac myocytes. The roughly cylindrical adult myocyte can grow either in width (diameter) or length, resulting in thickened ventricular walls or chamber dilation, respectively. In theory, concentric myocyte growth increases the width of cardiomyocytes, inducing parallel assembly of sarcomeres and thereby reducing ventricular wall stress (Law of LaPlace). In contrast, eccentric myocyte growth increases cardiomyocyte length, inducing serial addition of sarcomeres to accommodate greater ventricular volumes without stretching individual sarcomeres beyond the optimum length for contraction (Frank-Starling Law). In pressure overload diseases, such as aortic stenosis or hypertension, there is increased systolic wall stress, and concentric hypertrophy initially predominates. In volume overload diseases, such as following a myocardial infarction or dilated cardiomyopathy, eccentric hypertrophy predominates, presumably in response to increased diastolic wall stress. A fundamental question being addressed in the Kapiloff lab is what confers the differential growth of the myocyte in width and length. We are identifying myocyte signaling pathways and transcription factors that are central to this phenotypic switch.