Basic and Clinical Studies to Understand the Role of the CD5L/AIM Protein in AMD

Francesco Giorgianni, PhD
The University of Tennessee Health Science Center (Memphis, TN)
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2019
Disease:
Macular Degeneration
Award Amount:
$160,000
Grant Reference ID:
M2016068
Award Type:
Standard
Award Region:
US Southern

This grant is made possible in part by a bequest from the Stuart Blydenburgh Trust.

Francesco Giorgianni, PhD

In Vitro and In Vivo Studies of CD5L/AIM as a Possible Key Role Player in Drusen Biogenesis

Summary

We have discovered that certain cells of the eye, termed retinal pigment epithelium (RPE), that are typically damaged in age-related macular degeneration (AMD), express a protein that is targeted by the immune system of patients who have AMD by means of auto-antibodies. This protein we discovered in the RPE is CD5 molecule-like protein/ apoptosis inhibitor of macrophage (CD5L/AIM). CD5L/AIM is a secreted scavenger receptor protein, and we have evidence suggesting that CD5L/AIM is very important in helping the RPE clear damaged lipoproteins (called oxidized low-density lipoproteins, or oxLDL) that accumulate under the RPE to form drusen deposits. The presence of drusen often is the first and most typical evidence that an eye has developed AMD. Thus, we will culture RPE cells in vitro to prove that CD5L/AIM is a key molecule in clearing oxLDL and that, when blocked by an antibody as happens with auto-antibodies in patients who have AMD, the RPE cells will no longer be able to clear oxLDL. Lastly, to understand how the presence of auto-antibodies in the bloodstream of patients with AMD relates to disease in affected patients, we will study serum samples from AMD patients and correlate the levels of anti-CD5L/AIM auto-antibodies with how many drusen they have at the back of their eyes, as well as with certain genetic factors that are known to increase the risk of developing AMD. This will allow us to test the hypotheses that the more auto-antibodies one has against CD5L/AIM, the more drusen we are likely to find at the back of the eye, which would suggest that certain auto-antibodies facilitate formation of drusen in patients who have AMD.

Details

The main objective of our research project is to reveal the cellular and molecular mechanisms involved in age-related macular degeneration (AMD) by studying two key pathological events that characterize AMD: the accumulation of drusen deposits and the death of retinal pigment epithelium cells (RPE). We expect that our work will provide new knowledge about the molecular pathways that underlie the formation of drusen in AMD; characterize a novel disease biomarker; and identify new therapeutic targets and strategies for AMD treatment.

We have established that patients with AMD present increased levels of auto-antibodies against a secreted scavenger receptor protein called CD5L/AIM (CD5 molecule-like protein/ apoptosis inhibitor of macrophage), which we discovered to be highly expressed in RPE cells. To date, the biological function of CD5L/AIM in the RPE is unknown. However, new evidence from our laboratory suggests that CD5L/AIM plays an important role in helping the RPE cells remove harmful accumulations of oxidized lipoproteins (oxLDL). RPE cells are typically damaged in AMD, and oxLDL builds up under the RPE cells to create drusen deposits that can induce an inflammatory response, leading to cellular death and retinal tissue damage.

Our first aim is to prove that CD5L/AIM is a key molecule in clearing oxLDL and that, when blocked by an antibody, analogous to what we believe happens with auto-antibodies in AMD patients, the RPE are no longer able to clear oxLDL, thus leading to drusen buildup. We are investigating how the function of CD5L/AIM in the context of oxLDL-induced damage influences the regulation of genes involved in metabolism/removal of oxidized proteins and lipids. These studies will help elucidate the exact molecular pathways that are involved in these mechanisms.

In the second aim, in order to understand how the presence of auto-antibodies in the bloodstream of patients with AMD relates to specific disease stages, we are analyzing serum samples from AMD patients and correlating the levels of anti-CD5L/AIM auto-antibodies with presence of drusen and with specific genetic markers known to increase the risk of developing AMD. This work tests the hypothesis that an increase in the levels of auto-antibodies against CD5L/AIM correlates with drusen levels, which would suggest that auto-antibodies against CD5L/AIM facilitate formation of drusen in patients with AMD.

Elucidation of the role of CD5L/AIM in drusen biogenesis and AMD pathogenesis will open new avenues for the design of therapies to modulate the removal and degradation of cytotoxic and pro-inflammatory oxLDL. In addition, our research will support the development of a new biomarker for early detection of AMD. These outcomes will make a significant contribution to the development of new treatments and cures that will improve quality of life for the millions of people impacted by this debilitating disease.

About the Researcher

Francesco Giorgianni, PhD, is assistant professor in the Department of Pharmaceutical Sciences at the University of Tennessee Health Science Center (UTHSC) in Memphis, TN. He completed his postdoctoral studies in the field of molecular pharmacology at St. Jude Children’s Research Hospital with Dr. Raymond Blakley. He worked on the development of enhanced forms of enzymes to be used in gene therapy treatment of pediatric cancers. After his training at St. Jude Children’s Research Hospital, he joined the laboratory of Dr. Dominic Desiderio, one of the pioneers and world experts in the field of biological mass spectrometry applied to the study of the regulatory mechanisms of the hypothalamic-pituitary-adrenal axis and neuroendocrine cancers. In Dr. Desiderio’s laboratory, Dr. Giorgianni developed new methods for the analysis of complex protein samples by LC-MS/MS. His work led to the discovery of various post-translationally modified forms of important hormones, including human growth hormone. As the assistant director of the UTHSC mass spectrometry core facility, Dr. Giorgianni became involved with several interdisciplinary research projects focusing on retinal degenerative disorders, including AMD. One of these collaborative projects with Dr. Alex Iannaccone, a prominent physician-scientist in the field of degenerative retinal diseases, became a turning point in Dr. Giorgianni’s scientific career. Together, they formed a multidisciplinary, synergistic partnership to tackle the mechanistic complexities of AMD and to translate new discoveries into clinical applications.

Personal Story

Early in the Giorgianni-Iannaccone collaboration, I attended a community event where I met patients affected by retinal disorders. I was struck by the unflinching determination and optimism that permeated each person’s story. Witnessing the real-life effects of the diseases that I have studied in the laboratory, and becoming inspired by the strength present in those who face these disorders, I am committed to helping find the cures for people battling debilitating eye disorders such as AMD.

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