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Federica del Monte

Professoressa associata

Dipartimento di Scienze Mediche e Chirurgiche

Settore scientifico disciplinare: BIO/11 BIOLOGIA MOLECOLARE

Temi di ricerca

Parole chiave: Scompenso Cardiaco Cardiomiopatie Omeostasi del Calcio Misfolding proteico Stress del Reticolo

My major activity is in basic and translational research. My laboratory research focuses on understanding the pathogenesis of heart failure (HF) and has evolved towards innovative unexplored territories. Our latest discoveries are recognized as a major breakthrough that opened a new era for the understanding of the pathogenesis of HF. In addition to devoting 70% of my time to research, and 30% to administrative activities, mentoring and teaching the new generations of clinician scientists and serving in the scientific community at national and international meetings, scientific associations and federal agencies.

Our initial work demonstrated the key role of SERCA2a in sustaining contractility, metabolism and survival from single cells-to large animal models. I am a recognized leader in cardiomyocytes physiology and Ca2+ handling in animal and human hearts and I am invited to provide lectures on the topic. For this I was awarded a Harvard Catalyst and a Harvard Stem Cell Institute award.

As principal investigator I discovered, in dilated cardiomyopathy (iDCM), plaque and tangles-like protein aggregates similar to the pathological defects in Alzheimer Disease (AD). We characterized the cell response to misfolded proteins and identified, in iDCM, genetic variants in common with AD changing the paradigm of the pathogenesis of iDCM. I am recognized nationally and internationally as leader in this new field. For these studies I was awarded a K08 award, a Harvard-Armenise International Award, an NIH R21 and a R01 grants. A number of publications to the one describing this work are under submission:

1. Balla C**, Subramanian K**, Egidy-Assenza G, Rota M, Volpe M, del Monte F. Presenilin-2, a novel EC-coupling protein, regulates Ca2+ cycling and contractility. European Heart Journal under submission. This work provides the first description of the mechanisms by with the loss of function of the cardiac isoform of presenilin (the gene associated with early onset Alzheimer Disease and now idiopathic dilated cardiomyopathy – see reference 64) affect myocardial function in vivo and cardiomyocytes in vitro. Under submission

2. Luciani, M, Troncone M, Balla C, Subramanian K, Egidy-Assenza G, Volpe M, Macgillivray TE, del Monte F. SR Ca2+ depletion induced by Presenilin deficiency attenuates the Unfolded Protein Response signaling pathways. In preparation. This will be the first report that describes the response of the failing human heart to protein misfolding (UPR) in the presence and absence of presenilin genetic variants. Under submission

3. Luciani, M, Gianni D, Bouzou B, Chan J, Johnson K, Dec WG, Macgillivray T, del Monte F. Unique idiopathic Dilated Cardiomyopathy gene expression profiling: relationship to neurodegenerative diseases. In preparation. This report will provide the first evidence that genetic changes associated with Down Syndrome play a role in the pathogenesis of idiopathic dilated cardiomyopathy. This study also let to the discovery of the role of stanniocalcin in the pathogenesis of AL amyloidosis published as ref 77.

A milestone in the discovery of the molecular mechanisms of AD was the purification and chemical characterization of amyloid fibrils. We decoded the molecular composition of cardiac plaques. We identified an actin-polymerizing protein (Cofilin-2) to be comprised within the aggregates and we characterized its role on cardiac function. For these studies I have been awarded an AHA Innovative Research Grant. A manuscript has been published on JACC describing this work:

1. Subramanian, K**, Gianni, D**, Balla, C**, Egidy Assenza, G., Joshi, M., Dec, W.G., Macgillivray, T.E., Van Eyk, J., Agnetti, G, Paolocci, N., Bamburg, J.R., Agrawal, P.B., del Monte F. Cofilin-2 Phosphorylation and Sequestration in Myocardial Aggregates: Novel Pathogenetic Mechanisms for Idiopathic Dilated Cardiomyopathy. JACC 2015; 65 (12): 1199-214.

A follow-up to this work is to understand the structural and dynamic changes imposed by post-translational modification to cofilin-1 and cofilin-2. For this work two manuscripts are under submission.

A new direction in the investigations of protein misfolding in cardiac disease also relate to the new concept of metastatic transmissibility of misfolded proteins. We therefore investigated the involvement of the heart in the overall pathology of Alzheimer’s disease. Also, clinical evidence links DCM and AD through analogous epidemiological and genetic profiles, biochemical characteristics and common triggers, including inflammation, oxidative stress and hypoxia. For this study a manuscript is under submission and one in preparation:

1. Mechanisms of toxicity of pre-amyloid oligomers using atomic force microscopy. Study participants: Bernini F**, Malferrari D, Borsari M, Castellini E*, del Monte F*. This work investigates the mechanism of spreading of pre-amyloid oligomers using atomic force microscopy and the results under submission. Scientific Reports (a Nature group journal) 2016 Oct 24;6:35865. doi: 10.1038/srep35865.

2. Troncone L, Luciani M, Coggins M, Ho CY, Smith N, Crain B, Frosh MP, del Monte F. Amyloid Ab pathology in Alzheimer’s Disease Hearts. A systemic disease or protein metastatsis? JACC 2016 Dec 6;68(22):2395-2407. doi: 10.1016/j.jacc.2016.08.073

We generated a high throughput platform for the study of the transcriptional factors in human hearts from normal and diseased tissue. For this work, we are also preparing the following manuscript: 1) Generation of a new high-throughput quantitative real-time PCR (Quantrrx) to study the human transcription factor expression in normal and diseases myocardium. This work was supported by the R21 award HL110042.

1. Kilianova A, Rowe G, Arany Z, del Monte F. Human transcriptome in idiopathic dilated cardiomyopathy - a novel high throughput screening. Under submission. Candidate transcription factors will be tested in follow-up studies that will generate new manuscripts and R01 grant applications

We recently begun investigating 1) the effect of air pollution in the oxidative stress induced protein aggregation in the heart and brain; 2) the mechanisms of exosome mediated peripheral proteotoxicity of Aβ. For this work, we were awarded an R01 and an AHA grant.

Given the commonality of the structure/function of misfolded proteins, the unfolding protein response and the protein degradation pathways the results obtained can be translated to any cell, offering a common therapeutic target for many diseases affecting millions of people.

Supporting activities for the cardiology division are mentoring students and fellows, from experience as reviewer for K08 and K99-R00 NIH grants.

At BIDMC I organized the weekly seminar series and organized (and lecturing at) the T32 educational seminar series. I was also appointed as a member in the Department of Medicine Committee on the Advancement of Women, I took part in the training course organized by Professor Zeidel for residents in Internal Medicine and General Surgery. The course is hold at the Mount Desert Island Biological Laboratories and is aimed at understanding of basic physiological concepts through hands-on experiments in a research laboratory. The course is organized around several research modules that examine all aspects the physiology of the body organ and how to translate the pathological changes within clinical cases. In each module, classical experiments using model systems (toad, zebrafish, roundworm, shark, Xenopus oocyte, in an evolutionary comparative approach) are combined with modern molecular techniques. The goals of the Squalus Cardiac Module are geared towards understanding the Starling Principle of the heart and appreciating the hormonal response of the heart to changes in preload and afterload. By way of a simple experimental design, students will have the opportunity to change the working conditions of the heart and see how this alters the cardiac function. This has clinical applicability particularly in thinking about how to care for patients with cardiogenic shock and those who demonstrate septic physiology with impaired cardiac function.

Since 2007 I have been invited to teach at one of the most prestigious courses at MIT (HST cardiovascular physiology).

In July 2017, I joined the Medical University of South Carolina. Here I have initiated and Direct the Heart and Brain program and the Cardiovascular biobank. The program represents the first program to study the mechanisms of protein misfolding and degradation linking diseases either as a systemic or metastatic condition from the bench side to the clinic. The biobank support my research as well as research of all investigators in the world. I have also been granted an academic license to initiate and interdisciplinary clinic to care for patients with a Heart Failure and Alzheimer’s Disease.