Sheel, A, Shao, R., Brown, C., Johnson, J., Hamilton, A., Oppenheimer, J., Smith, W., Visconti, P., Markstein, M., and Schwartz, L.M. (2019) Skeletal Muscles Do Not Undergo Apoptosis During Either Atrophy or Programmed Cell Death-Revisiting the Myonuclear Domain Hypothesis. We are currently expanding this analysis to examine skeletal muscle disorders in mammals. Recently, we performed a comprehensive RNA-seq transcriptomics analysis of both the mRNAs and small RNAs to identify all of the differentially expressed genes, as well as the microRNAs that regulate their stability and translatability. The ability of the ISMs to commit suicide requires de novo gene expression, and we have use a variety of molecular techniques to clone death-associated transcripts from these cells. These giant cells are used to propel the moth out of the pupal cuticle at the end of metamorphosis, and then they die during a 30 hr period in response to a specific hormonal trigger. To define the molecular mechanisms that mediate this process, we have exploited the intersegmental muscles (ISM) of moth as a model system. Defects in the regulation of cell death serves as the basis of many human diseases, including auto-immunity, neurodegeneration and most cancers. Because these cells are particularly susceptible to insult in the early stages of AMD, it will be interesting to see whether RPE alterations precede or result from reductions in choriocapillaris perfusion.Programmed cell death is a fundamental component of development and homeostasis in virtually all organisms. While our initial application of AOSLO imaging has been limited to visualization of photoreceptors, we are now imaging retinal pigment epithelial (RPE) cells. For patients with dry AMD and macular atrophy, AOSLO has shown that photoreceptor density overlying regions of reduced choriocapillaris perfusion is reduced however, when choriocapillaris perfusion is normal, so too, is the overlying photoreceptor density. Similarly, in wet AMD, OCT-A reveals that there is choriocapillaris hypoperfusion bordering choroidal neovascularization. Outside of this surrounding region, choriocapillaris perfusion appears normal. In macular atrophy, OCT-A shows a surrounding region of reduced choriocapillaris blood flow. In both dry AMD with macular atrophy and in wet AMD, OCT-Areveals dramatic reductions in choriocapillaris perfusion. Our imaging efforts have revealed striking alterations of the choriocapillaris in patients with advanced AMD. By imaging the choriocapillaris and overlying macular retina, we hypothesize we can determine whether visual loss in AMD is primarily due to vascular disease, or alternatively, is caused by a primary cellular degeneration. AOSLO provides high-resolution visualization of photoreceptors that are damaged in advanced AMD. OCT-A images the outer retinal blood supply, the choriocapillaris, which atrophies in advanced AMD. The purpose of our Network grant is to use optical coherence tomography angiography (OCT-A) and adaptive optics scanning laser ophthalmoscopy (AOSLO) to better understand what causes visual loss in age-related macular degeneration (AMD).
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