Regenerative Medicine Scholarly Pathway

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Inside Our Labs: Behind the Scenes of Regenerative Medicine

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Welcome MS1 MD students!

 

The Regenerative Medicine Scholarly Pathway is divided into 4 Subspecialized Pathways:

 

#1 Cell and Gene Therapy

 

#2 Cell Transplantation


#3 Transplantation Immunology

#4 Induced Pluripotent Stem Cells (IPSCs)

 

Pathway Goals:

 

#1 Gene Therapy

After the course, the students should be able to:

  1. Explain mechanisms that are involved in viral gene integration in mammalian cells.

  2. Apply their knowledge in molecular biology to genetic modification of mammalian cells. This means they should be able to develop cloning strategies for your gene of interest into a viral vector and propose a strategy for in vivo genetic manipulation.

  3. Apply their knowledge in single gene disorders and develop treatment schemes for patients with these disorders using gene therapy.

#2 Cell Transplantation

After the course, the students will be able to:

  1. Describe the basics of stem cell biology, different types of stem cells and the immunological mechanisms behind engraftment and rejection, and how tolerance develops after transplantation.

  2. Extract and integrate information from state-of-the-art lectures in combination with overview articles and literature searches on the internet within the research field.

#3 Transplantation Immunology

After the course, the students are expected to be able to:

  1. Discuss immunological principles of relevance to transplantation and relate those to normal immunological reactions.

  2. Relate relevant methods used for investigations and diagnosis in relation to stem cell and organ transplantation.

  3. Discuss the cutting-edge of preclinical transplantation research.

  4. Discuss diagnostic principles before and after transplantation that are under development.

  5. Give a historical perspective of clinical and preclinical transplantation.

  6. Reflect over the future of clinical transplantation immunology.

#4 Induced Pluripotent Stem Cells (IPSCs)

After the course, the students are expected to be able to understand how:

  1. Patient-specific iPSCs, and the differentiated products, can help to better understand pathogenic mechanisms that underlie disease.

  2. Patient-specific iPSCs can serve as a source of autologous cells for transplantation therapies.

10 Mentors:
Students can pick the mentor/project that aligns with their career goals and passion. There will be an application process explained on the day of the Scholarly Concentration Fair (Oct 13th 2020).

1) Chunming Dong, MD:

 

 

 

 

 

 

Research Summary: 

My research spans from genomics, epigenetics, to molecular and cellular biology, as it relates to cardiovascular disease (CVD).  My major focuses are atherosclerosis and the dysfunction of endothelial progenitor cells (EPCs)—a form of stem cells derived from the bone marrow and circulating in the peripheral blood—in the contexts of biological aging, smoking, HIV infection and cocaine abuse.  Indeed, I have had multiple Federal and State grants to study the in-depth molecular mechanisms, focusing on microRNAs, underlying EPC dysfunction in aging, smoking and HIV infection.  Over the last 5 years, my research has expanded to study the molecular mechanisms that underlie cocaine-induced cardiovascular disease (CVD) using small RNA and RNA sequencing and functional genomics.  We are also investigating the use of extracellular vesicles (EVs)/exosomes and EV RNA sequencing to identify EV-microRNA (EV-miR) candidates that predict CVD in people living with HIV (PLHIV) and use EV injections to reconstitute the effects of HIV infection in the cardiovascular system.  Furthermore, we have generated tailored EVs that carry modified EV-miR cargo by genetically engineering mesenchymal stromal cells (MSCs) and have successfully used these tailored EVs to treat CVD.

 

Research Projects: 

  1. Study the role of plasma EVs in meditating the effects of HIV infection in the development of HIV-associated accelerated CVD and the use of tailored EVs to prevent/treat CVD.

  2. Investigate the microRNA-mRNA pathways that regulate the cocaine effects in the cardiovascular system.

  3. Use CRIPR-Cas9 technology to knockout MHC molecules to create universal organs for allograft transplantation. 

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2) Dr. Derek Dykxhoorn, PhD:

Research Summary: 

Research in the Dykxhoorn laboratory focuses on understanding the molecular and cellular mechanisms that underlie a variety of neurological disorders including neurodevelopmental, neurodegeneration, and sensorineural disorders. To that end, we apply novel stem cell based models of neurons, glial cells, and organoids to study the role of specific genetic variants in disease development. The ultimate goal of these experiments is to identify therapeutic targets that will effectively restore/normalize cellular functional and abrogate the development of these diseases, including the application of high content screening approaches along with genome editing approaches.

 

Research Projects:

  1. Study the role of genetic variants in Alzheimer-associated genetic variants play in disease development.

  2. Understand the role of the excitation/inhibition balance in proper neuronal development in autism and epilepsy.

  3. Genome engineering and cell-based therapeutic strategies in the treatment of sensorineural hearing loss

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3) Dr. Joshua Hare, MD:

Research Summary: 

Our goal is to develop better understanding and treatments for heart disease. Our lab utilizes multiple approaches, ranging from cell culture to animal models to clinical trials. We perform mechanistic studies focusing on the cellular and molecular effects of nitric oxide (NO), novel pharmaceutical agents and cell therapy. Our studies revealed that NO influences normal and pathologic cardiac physiology, and signals in a complex manner through interactions between NO and reactive oxygen species, a process termed nitroso-redox balance. We have determined that Growth Hormone Releasing Hormone Receptor agonists have beneficial effects in large and small animal models of myocardial infarction, and we expect to move them into clinical trials in the near future. We have a longstanding interest in the pathophysiology and clinical manifestations of dilated cardiomyopathy (DCM), particularly the role of immunological activation and the microarray/transcriptomic profile of patients as a cause/diagnosis of DCM. Our significant experience with adult stem cells, including induced pluripotent stem cells (iPSCs), spans the gamut from basic research to clinical trials.

 

Research Projects: 

1.    Analysis of cardiac structure and function from small and large animal studies, e.g. magnetic resonance imaging, pressure volume loops, echocardiography, histology.

2.    Manipulation of iPSCs and analysis of their differentiation into cardiomyocytes.

 

 

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4) Dr. Robert Levy, PhD:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Research Summary

Allogeneic hematopoietic stem cell transplantation (aHSCT) is a potentially curative therapy for a number of hematologic malignancies including acute myeloid leukemia (AML) and relapsed/refractory non-Hodgkin lymphoma (NHL). Unfortunately, graft vs host disease (GVHD) remains a serious clinical problem post-aHSCT which threatens anti-tumor (GVM) immune function and patient survival. As the number of aHSCTs rises, the need for better strategies to treat GVHD, while preserving the GVM response, remains paramount. The Levy lab is developing novel approaches to suppress GVHD while maintaining GVL. Our collaborative work with the Komanduri lab discovered that targeting the MEK pathway using a 3rd generation MEK inhibitor, trametinib specifically inhibits allo‐reactive naïve and early memory T cells, while sparing pathogen‐ and cancer‐specific donor T cells critical for GVM post‐HSCT (Blood, 2013, PMC3674663; JCI Insight, 2016, PMC5033881). Building on these findings, we recently discovered a novel 2-pathway strategy for FoxP3+ Treg expansion in donors which spares GVM while suppressing GVHD (Biol Blood Marrow Transplant, 2017, PMC5625339 and 2018, PMID: 29751114). Recent work demonstrates their Treg strategy is superior to post‐transplant cyclophosphamide (PTCy) for GVHD prophylaxis (JCI Insight, 2018 in revision). Based on the role of STING in modulating anti-tumor immunity, the Levy labs explored the role of STING in promoting the development of GVHD and discovered that GVHD following matched (“MUD”)  HSCT is reduced in the absence of STING and worsened using STING agonists suggesting that inhibition of STING in recipient cells can be a novel strategy to reduce GVHD and maintain GVM (Sci Transl Med. 2020 Jul 15;12(552):eaay5006. doi: 10.1126/scitranslmed.aay5006.PMID: 32669421; https://medicalxpress.com/news/2020-07-sylvester-protein-ease-graft-host.html,) 

Click here to see 2-slide summary and 7-minute video by Dr. Levy!

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5) Dr. S. Shelby Burks, MD:

 

 

 

 

 

 

 

 

Our lab focuses on severe peripheral nerve injury. We are housed in the Miami Project to Cure Paralysis. Research focuses on the use of Schwann cells and Schwann cell products (exosomes) and their ability to enhance peripheral nerve recovery. We have partnered with industry and federal funding agencies to investigate this in both clinical and preclinical models. Along these lines we are investigating a second generation, three-dimensional nerve conduit which can function as a cell delivery device. In addition to functional recovery we are also evaluating novel pain and sensory outcomes.  

Pre-clinical / animal research 

1.       The use of three-dimensional axon guidance channels to enhance peripheral nerve recovery.  

2.       Optimization of Schwann cell and Schwann cell products to enhance. 

3.       Optimization of nerve repair techniques and cellular transplantation strategies to reduce neuropathic pain after injury. 

Clinical / human subject research 

4.       Autologous Schwann cell transplantation in severe peripheral nerve and brachial plexus injury.  

5.       The use of nerve transfers in cervical spinal cord injury. 

Medical students interested in working in our laboratory will work closely with our post-doctoral fellow Emily Errante PhD. Please do not hesitate to reach out to me directly with questions: S. Shelby Burks MD – sburks@med.miami.edu.  

https://scholar.google.com/citations?user=Djq8TR8AAAAJ&hl=en 

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6) Dr. Lina A Shehadeh, PhD:

 

 

 

 

 

 

 

 

 

 

 

 

Research Summary:

Click here to check out projects at the Shehadeh Lab.

 

Research Projects:

  1. Screening of FDA-approved drugs to identify best candidates for reducing LDL cholesterol influx. The assay employs Alport patient-derived iPSCs differentiated into renal tubular epithelial cells, and live cell imaging.

  2. Screening of FDA-approved drugs to identify best candidates for inducing cardiac regeneration (endogenous adult cardiomyocyte division). The assay employs mosaic analysis with double markers (MADM) mice in which cardiomyocyte division is evidenced by single colored red or green daughter cells.

  3. Screening of FDA-approved drugs (and other reagents) to identify best candidates for reducing SARS-Co-V2-spike bearing pseudoviral infection. The assay employs inoculation with pseudovirus in various human cell lines, and live cell imaging.

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7) Dr. Roberto I Vazquez-Padron, PhD:

 

 

 

 

 

 

 

 

 

 

 

 

Research Summary:

My research focuses on the cellular and molecular mechanisms underlying obstructive vascular diseases like atherosclerosis, in-stent restenosis, transplant vasculopathy, and arteriovenous fistula failure. In particular, my laboratory aims at understanding the role of integrins, tyrosine kinases, and ECM modifying enzymes in the phenotypic switching and growth of constituent cells in arterial and venous walls in response to physiological and pathological cues. The work of my research group involves human studies and cellular and in vivo models. As a basic scientist with many clinical collaborators, my overall goal is to provide a better molecular understanding of these diseases so that improved vascular therapies can be designed.

 

Research Projects:

  1. The role of microbiome in Inflammatory Bowel Disease related atherosclerosis.

  2. Catheter infections and vascular diseases

  3. The role of Lysyl Oxidase in vascular calcification

8) Dr. Karen Young, MD, MS:

 

 

 

 

 

 

 

 

 

 

 

 

Research Summary:

Dr. Young’s laboratory is housed in the Batchelor Children’s Research Institute. Her lab’s primary focus is understanding the molecular and cellular mechanisms that lead to endothelial dysfunction in preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Her current projects involve 1) defining the mechanisms by which mesenchymal stem cell cells and their exosomes reduce BPD/PH, 2) elucidating whether endothelial progenitor cell mitochondrial dysfunction is a common major cellular pathway that links neonatal intermittent hypoxia episodes to long-term endothelial dysfunctional states and impaired cardiopulmonary outcomes, 3) defining the role of aging pathways in BPD/PH pathogenesis and 4) understanding the molecular mechanisms that link placental dysfunction to BPD/PH.  Over the past 2 decades, Dr. Young has mentored many undergraduates, medical students, residents, and fellows, many of whom have received research awards and themselves become leaders and mentors.

9) Dr. Ralf Paus, MD:

 

 

 

 

 

 

 

 

 

 

 

 

Research Summary:

The Paus works on the human hair follicle as a regenerative and reparative model  organ, with translational emphasis on alopecia areata, scarring alopecias, and chemotherapy-induced alopecia as well as on epithelial skin stem cells, skin rejuvenation, skin neurobiology & neuroimmunology, and cutaneous neuroendocrinology. Their main research models are human skin and hair follicle organ culture as well as the analysis of humanized

mouse models.

10) Dr. Thomas Best, MD:

 

 

 

 

 

 

 

 

 

 

 

 

Research Summary:

ADVANCED STEM CELL TECHNOLOGIES (ASCT) LAB

MAIN GOAL:

The overarching goal of the ASCT lab is to advance cell therapies using adult Mesenchymal Stem Cells (MSC) by addressing key aspects of the manufacturing of a cell-based product. The areas of interest span from processing of the cells to their delivery to the patient, with special attention to the current regulatory concepts from the Food and Drug Administration (FDA) agency. On this basis, our main focus is ‘MSC signatures’ which are directly related to specific MSC functions in vivo for effective musculoskeletal therapeutics.

PROJECTS: We investigate the MSC responses to environmental stimulation & functional subpopulations. On this basis, various projects are directed at understanding how MSC sense their immediate microenvironment and respond molecularly as part of their so-called ‘Medicinal activities’. Specifically:

- Identification and characterization of distinct phenotypic mesenchymal stem cell (MSC) subpopulations within crude preparations isolated from bone marrow (BM), infrapatellar fat pad (IFP), adipose (ASC), umbilical cord (UC) and endometrial (endo) tissues. Secondary to this, to understand how these distinct “signatures” impact their performance as cell progenitors, immunomodulators and trophic effectors during cell-based therapy, developing ex vivo protocols to reduce the innate product heterogeneity by inducing “more uniform” functional phenotypes with specific attributes.

- MSC intercellular communication mechanisms through exosomes-type of extracellular vesicles during immunomodulation and tissue repair, and ways to “tailor” their signaling cargo by processing parental MSC.

- Generation of novel ways to deliver MSC (e.g., 3D structures) that maintain and protect the beneficial induced phenotypic features (anti-inflammatory, anti-fibrotic, analgesic).

- Development of potency assays to predict MSC efficacy ex vivo that result from the identified functional signatures.

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