Joseph F. Arboleda-Velasquez, M.D., Ph.D.

Harvard Medical School

Assistant Professor of Ophthalmology

Schepens Eye Research Institute of Massachusetts Eye and Ear

Assistant Scientist

Research Summary

Center/Research Area Affiliations

Biography

Dr. Arboleda-Velasquez studies the cell signaling mechanisms that control the integrity of the vasculature in a diabetic environment. He uses novel technologies to study cell-cell and protein-protein interactions and uses imaging methods and enzymes to explore the cell signaling circuitry underlying diabetic microangiopathy. In addition, he is investigating novel mechanisms that contribute to proliferative diabetic retinopathy, using patient-derived cell cultures and next-generation sequencing approaches. This research may lead to therapeutic approaches for diabetic retinopathy, which stands as the most prevalent cause of blindness in working adults.

Download his CV [PDF] for more information.

Education

M.D., University of Antioquia, Medellin Colombia (2000)
Ph.D., Harvard Medical School (2009)

Postgraduate Training

Research Fellowship, Schepens Eye Research Institute of Mass. Eye and Ear (2010-2011)

Honors

2015: Young Mentor Award, Harvard Medical School
2015: Leadership Development for Physicians and Scientists Program, Harvard Medical School
2015: Early Career Institute in Neuroscience Travel and Mentoring Minority Award, NINDS-University of Pittsburg
2012: Carl Storm Underrepresented Minority Fellowship, Gordon Research Conference
2011: Society of Neuroscience Scholar Fellow Award

His Story

Pathophysiology of Small-Vessel Diseases

Dr. Arboleda-Velasquez is interested in studying the biology and pathophysiology underlying small-vessel diseases (SVDs), such as diabetic retinopathy. SVDs are prevalent systemic conditions that affect many organs, including the retina, brain, kidneys, and other richly perfused tissues.

His current research program encompasses two areas—one that arises from his previous research on cell signaling and the pathobiology of a SVD named CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a neurological syndrome associated with stroke, and a second that addresses the pathogenesis of diabetic retinal disease.

Notch Signaling and Diabetic Retinopathy

Diabetic retinopathy is among the most common and devastating complications of diabetes. Clinical and experimental observations indicate that interactions between endothelial cells (ECs) and pericytes— the two cell types that form capillaries—are central to the integrity and function of the retinal vasculature. Loss of pericytes in background diabetic retinopathy is temporally associated with endothelial dysfunction.

A central hypothesis of his research is that Notch signaling regulates cellular and molecular processes essential for microvascular differentiation and stability. Basement membrane thickening and pericyte loss are early changes associated with the development of diabetic retinopathy, and these events could disrupt Notch signaling, which depends upon juxtaposition of cellular membranes.

To test this hypothesis, he is establishing a cell culture system that will allow him to investigate pericyte/endothelial cell interactions mediated by the Notch receptor and its ligands and examine whether a diabetic environment affects these interactions. To achieve this goal, he is using traditional vascular cell co-culture methods, novel technologies that allow for imaging of protein-protein interactions across cellular interfaces, and mouse models.

The CADASIL project focuses on evaluating translational approaches, in which he aims to test whether manipulation of the Notch signaling pathway could rescue vascular degeneration in animal models of the disease. This research may lead to therapeutic approaches for this devastating syndrome that affects hundreds of families around the world.

Projects

Research Interests

  • Mechanisms of small vessel diseases, including diabetic retinopathy

Cellular and Molecular Basis of Diabetic Retinopathy

Many patients with diabetes develop vascular abnormalities in their retinas—a disease called diabetic retinopathy—that can lead to vision impairment and blindness. Dr. Arboleda-Velasquez is studying the cell signaling mechanisms that control the integrity of the vasculature in a diabetic environment.

There is overwhelming evidence that VEGF, TGFβ, PDGF, Notch, and other molecules that are essential for vascular formation, are also part of the cell signaling circuitry contributing to vessel maintenance and the cellular response to injury and metabolic change. However, very little is known about how different signaling pathways are integrated in the microvasculature cell program and even less is understood about how these cell communication mechanisms are challenged in diabetes.

  • Do these signaling molecules operate through the same molecular targets during development and in the adult?
  • Which molecules predominate?
  • In what order do they function in the process of vascular remodeling in response to a high-glucose environment?
  • How can we devise therapeutic approaches through manipulation of a signaling pathway without interfering with the function of other interconnected signaling mechanisms?

Dr. Arboleda-Velasquez uses novel technologies, imaging methods, and enzymes to study cell-cell and protein-protein interactions. It is widely known that catalysis depends on transient interactions between enzymes and their substrates. Scientists have recently taken advantage of this chemistry to design tools for the study of protein-protein and cell-cell interactions. These powerful methods can now be used to visualize known protein-protein interactions, to discover new protein-protein interactions in cell lysates, and even to label and measure protein-protein interactions across intercellular contacts.

Dr. Arboleda Velasquez is currently using these technologies to investigate how a diabetic environment could impact interactions of vascular cells mediated by the Notch signaling pathway. Notch proteins and their ligands help cells to communicate with each other through close range interactions, which could be impaired in diabetic patients as vessels degenerate.

Notch Signaling in Ischemic Cerebral Small-Vessel Disease and CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a frequent cause of stroke and cognitive decline in adults with a family history of these conditions.

CADASIL is caused by mutations in a gene called Notch 3. The Notch 3 gene is part of a group of genes that help cells communicate with each other. Cells use these social cues from neighboring cells as useful information to make decisions regarding their fate. However, it is not clear how Notch 3 mutations lead to cell-cell miscommunication and how this leads to stroke.

Dr. Arboleda-Velasquez uses mouse models of CADASIL and culture cells derived from these animals to study how CADASIL mutations affect Notch 3 function and how normal physiology could be restored using genetic manipulations and newly developed drugs. This work may lead to the identification of novel therapeutic targets for CADASIL, as many drugs that modulate Notch signaling are currently under development for other human conditions.

Publications

Selected Publications

 View his publications on PubMed.

  1. Arboleda-Velasquez JF, Valdez CN, Marko CK, D'Amore PA. From pathobiology to the targeting of pericytes for the treatment of diabetic retinopathy.Curr Diab Rep. 2015 Feb;15(2):573.
  2. Valdez CN, Arboleda-Velasquez JF, Amarnani DS, Kim LA, D'Amore PA. Retinal microangiopathy in a mouse model of inducible mural cell loss.Am J Pathol. 2014 Oct;184(10):2618-26
  3. Arboleda-Velasquez JF, Primo V, Graham M, James A, Manent J, D'Amore PA. Notch signaling functions in retinal pericyte survival. Invest Ophthalmol Vis Sci. 2014 Jul 11;55(8):5191-9.
  4. Arboleda-Velasquez JF, Manent J, Lee JH, Tikka S, Ospina C, Vanderburg CR, Frosch MP, Rodríguez-Falcón M, Villen J, Gygi S, Lopera F, Kalimo H, Moskowitz MA, Ayata C, Louvi A, Artavanis-Tsakonas S. Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease. Proc Natl Acad Sci U S A. 2011 May 24;108(21):E128-35.
  5. Brass SD, Smith EE, Arboleda-Velasquez JF, Copen WA, Frosch MP. Case records of the Massachusetts General Hospital. Case 12-2009. A 46-year-old man with migraine, aphasia, and hemiparesis and similarly affected family members. N Engl J Med. 2009 Apr 16;360(16):1656-65.