Professor ottavio arancio biography

The research of my laboratory is answering the following questions:. Epigenetic mechanisms: We are exploring steps affected at the downstream level of CREB phosphorylation. CREB plays an important role together with CBP in gene transcription through histone acetylation leading to the loss of chromosomal repression and transcription of genes needed for synthesis of proteins underlying memory formation.

Chromatin changes do not have to be necessarily limited to histone acetylation. As a mechanism which can "lock in" particular states of pathological gene expression in human cells, DNA methylation is an obvious candidate for contributing to the inexorably progression and irreversibility of AD in the middle to late stages of the disease. Additionally, DNA methylation may act early in AD, as some very recent work has shown that the proper regulation of gene expression in memory formation is not only controlled by the transcriptional machinery but also modulated by epigenetics.

We are investigating if SUMOylation plays a role in learning and memory. All this work would be incomplete without the goal to move each project forward to the stage where it not only provides new biological insights but also, when appropriate, serve as the basis for future development of new therapeutic strategies. Such translational research is enhanced by collaborations with medicinal-chemists, biotech specialists, pathologists and clinicians.

These studies should lead to the design of novel therapeutic approaches that might be effective in preventing or delaying the onset of AD and other neurodegenerative diseases characterized by cognitive disorders. Karen Duff, PhD Understanding the Molecular Basis of Neurodegenerative and Neuropsychiatric Diseases In general, we are exploring what goes wrong in the brains of patients with neurodegenerative diseases, especially Alzheimer's disease AD and Frontal Temporal lobe Degeneration linked to tauopathy FTD-tau with the overall aim of identifying therapeutic approaches that may be beneficial for the treatment, or prevention of these diseases.

Given our broad interest in neurodegenerative disease etiology and the insights to be gained by studying different diseases my lab has created various mouse models for the study of AD amyloid accumulation , tauopathies and synucleinopathies. These models have facilitated the study of many aspects of pathogenesis from how the disease propagates through the brain, to imaging studies allowing the examination of structural and functional changes in the brain in living animals, to the identification of relevant druggable pathways and the testing of drugs.

Our current interests are fourfold- the propagation of disease through the brain, the impact of ApoE4 on disease risk, the impact and restoration of functional clearance mechanisms and the basis and manipulation of memory deficits using optogenetic and brain stimulation techniques. Lloyd Greene, PhD Neuronal Differentiation The overall goal of research in this laboratory is to understand the mechanisms whereby neuronal precursors differentiate into mature functional neurons.

To this end, we use the rat PC12 pheochromocytoma cell line developed in this laboratory as a model system to study the mechanism of action of nerve growth factor NGF and the steps that lead to neuronal differentiation. Among current projects in the laboratory are those addressing the following questions: 1 What is the essential property of the high-affinity NGF receptor that permits it to mediate the functional activities of NGF and how is this receptor different from the low-affinity, non-functional NGF receptor?

What are the molecules involved in this effect? By what pathways are they regulated? Ulrich Hengst, PhD Local protein synthesis in developing and degenerating neurons Neurons are arguable the cells with the most extreme morphological polarization, with distances between the periphery and the neuronal cell bodies ranging from millimeters to several feet.

This extreme architectural polarization is mirrored in the existence of functionally distinct subcellular compartments, chiefly dendrites, axon, and soma. Spatially restricted protein expression is crucial for the establishment and maintenance of polarized neuronal morphology and function. Indeed, it has become apparent that alterations of polarized protein expression can cause or contribute to the pathogenesis of a wide variety of disorders.

Our laboratory studies the physiological role of intra-axonal translation during development as well as the possible role of local protein synthesis during neurodegenerative disorders, especially Alzheimer's disease. We seek to understand how changes in local protein synthesis can either attenuate or ameliorate neuronal integrity in AD brain. Tae-Wan Kim, PhD Molecular Mechanisms and Translational Research in Alzheimer's Disease The major goal of our laboratory is to understand the molecular basis of Alzheimer's disease AD using a multidisciplinary approach based on molecular, cellular and chemical biology.

We are also conducting translation research aimed at discovery and pre-clinical development of novel therapies for AD. Several cellular disease models are being used, including mouse embryonic stem ES cell-derived neurons as an alternative to primary cortical neurons for small molecule screening and functional genetic analyses. Relevant mouse models are also being utilized.

The first theme of our research is to understand the fundamental biochemical and cellular defects associated with the familial forms of AD, which occur in a small, but significant proportion of AD cases. Although familial AD FAD accounts for a small percentage of all AD cases, at the neuropathological level it is phenotypically indistinguishable from the more common sporadic form of AD.

Thus, understanding the genotype-to-phenotype transition in presenilin-dependent FAD is likely to shed light on the pathogenesis of the more common, non-familial AD. Mutations in the genes encoding the presenilins PS1 and PS2 are the most common cause of early-onset FAD and give rise to multiple cellular deficits. We investigate the molecular basis for the multi-functional nature of the presenilins as regulators of both intracellular ion homeostasis and intramembrane proteolysis.

Our recent studies reveal that alterations in phosphatidyl-4,5-bisphosphate [known as PI 4,5 P2], a phosphoinositide lipid that controls several essential neural functions, contributes to the biochemical and cellular defects associated with AD. This project is being conducted in close collaboration with the laboratory of Dr. Gilbert Di Paolo.

We have conducted a high throughput cell-based assay and identified small molecules that can modulate BACE1 function via either a direct or indirect mechanism. Using these chemical probes, our laboratory is trying to understand the mechanism of BACE1 regulation by identifying cellular target s of these novel chemical modulators of BACE1.

Furthermore, some of the small molecule hits are being developed as therapeutic candidates for the treatment of AD. Complementary to the chemical biology approach, biochemical experiments to isolate the BACE1-haboring molecular complex have been conducted. Several BACE1-associated proteins, including members of the sorting nexin and sortilin families of protein trafficking modulators, have been identified.

Professor ottavio arancio biography

The function and pathological relevance of these proteins are being investigated. Moreover, in additional studies, we are currently investigating the involvement of PP2A in traumatic brain injury, another condition that is associated with memory disorders and tau pathology. Does amyloid-beta play a critical positive role in synaptic plasticity and memory?

Recent research performed in my laboratory has shown that low levels of amyloid-beta similar to those present in the brains of healthy individuals throughout life, enhance synaptic plasticity and memory. Mauro Fa' is continuing these studies by addressing the following questions: can we visualize release of endogenous amyloid-beta and follow its fate in normal physiological conditions?

Does release of amyloid-beta from intracellular pools account for the increase in amyloid-beta following activity in the presynaptic terminal? In addition, in collaboration with Taub colleague Andy Teich, we are defining whether the locus of action of amyloid-beta is pre- or post-synaptic. Most importantly, a fundamental question originating from the discovery of a positive function for amyloid-beta is: how does it happen that a molecule performing a positive function gains a new and negative function?

To this end, Jordano Brito Moreira is testing whether changes in DNA methylation are responsible for expression of genes that reversibly or irreversibly are responsible for the disease onset. It is also by keeping my mind open that I hope to provide an original contribution to research on mechanisms of synaptic plasticity and memory, and particularly to discovering the causes of AD.

All this work would be incomplete without the goal to move each project forward to the stage where it not only provides new biological insights but also, when appropriate, serves as the basis for future development of new therapeutic strategies. Such translational research is enhanced by collaborations with Dr. Deborah Pre' and Vorapin Chinchalongporn, in collaboration with Dr.

Noggle, are determining whether stem cell technology can reproduce synaptic dysfunction using human derived fibroblasts. With Dr. These studies should lead to the design of novel therapeutic approaches that might be effective in preventing or delaying the onset of AD and other neurodegenerative diseases characterized by cognitive disorders.

Members of the Arancio Laboratory include, top row from left: Andrew F. Staining of induced pluripotent stem cell-derived neurons used to investigate neurotransmitter release.