Every year, Massachusetts General Hospital gives Physician-Scientist Development Awards to MD and/or PhD investigators who belong to groups considered underrepresented in academic medicine (from racial and ethnic populations that are underrepresented in the medical profession relative to their numbers in the population). The awards are intended to increase opportunities for URiM researchers to advance to senior positions in academic medicine at Mass General
The National Institute of Health (NIH) has encouraged institutions and organizations to prioritize biomedical, behavioral, and social sciences opportunities for individuals from underrepresented racial and ethnic groups. Based on data by the National Science Foundation, groups that are underrepresented in medicine (URiM) include: Blacks or African Americans, Hispanics or Latinos, American Indians or Alaska Natives, Native Hawaiians and other Pacific Islanders.
This year, four investigators received Physician-Scientist Development Awards, please join us in congratulating them!
Type 1 diabetes (T1D) is a chronic metabolic disease, where autoimmune cells destroy insulin-producing beta cells of the pancreas, resulting in insulin deficiency and hyperglycemia. Even with strict glucose monitoring and insulin replacement therapy regimens, T1D patients can still experience high premature death rates compared with the general population, predominantly from heart complications.
Dr. Alagpulinsa’s research examines how the bone marrow, which makes immune cells, can be impaired in T1D. This impairment can cause inflammation, insulitis (a disease of the pancreas caused by the infiltration of immune cells) and heart complications. His research aims to harness these insights to restore the function of insulin-producing beta cells and promote cardiovascular repair.
Dr. Alagpulinsa's Abstract:
Redirecting and recruiting endogenous stem/progenitor cells and immunoregulatory cells for in situ islet regeneration in type 1 diabetes
Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing beta cells of the pancreatic islets, resulting in insulin deficiency and hyperglycemia. The incidence of this incurable disease is on a global rise, affecting millions of people worldwide.
Even the strictest blood glucose monitoring and insulin injection regimen, which is the current gold standard of care, does not achieve tight physiological glucose control in the majority of patients. Consequently, most patients ultimately succumb to T1D-related complications.
The human bone marrow (BM) is endowed with stem and progenitor cells and regulatory T cells (Tregs) that have the capacity to abrogate the autoimmune response against beta cells, while supporting their regeneration. Unfortunately, the BM is also “sick” in T1D, causing impaired function and peripheral mobilization, which promotes inflammation and insulitis.
The overall goal of this research project is to understand how T1D impacts the BM environment using single-cell RNA sequencing analysis and to design pharmacological tools to efficiently mobilize BM stem and progenitor cells and Tregs into the blood circulation and islet-targeting nanoparticles loaded with chemokines to recruit these cells specifically into the islets to dampen the autoimmune response and elicit beta cell regeneration to treat T1D.
Dr. Ufere is currently in her postdoctoral research fellowship in gastroenterology. She focuses on health services and outcomes research in hepatology centering around palliative care and informed decision-making for patients with advanced liver disease. She looks forward to an academic career dedicated to developing interventions aimed at improving the quality of life and end-of-life care for patients with advanced liver disease and their caregivers.
Dr. Ufere's Abstract
Redirecting and recruiting endogenous stem/progenitor cells and immunoregulatory cells for in situ islet regeneration in type 1 diabetes
Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing beta cells of the pancreatic islets, resulting in insulin deficiency and hyperglycemia. The incidence of this incurable disease is on a global rise, affecting 64, 000 Americans annually and causing an annual loss in income and healthcare expenditure of $14.4 billion to the country. Even the strictest blood glucose monitoring and insulin injection regimen, which is the current gold standard of care, does not achieve tight physiological glucose control in the majority of patients. Consequently, most patients ultimately succumb to T1D-related complications. The human bone marrow (BM) is endowed with stem and progenitor cells and regulatory T cells (Tregs) that have the capacity to abrogate the autoimmune response against beta cells, while supporting their regeneration. Unfortunately, the BM is also “sick” in T1D, causing impaired function and peripheral mobilization, which promotes inflammation and insulitis. The overall goal of this research project is to understand how T1D impacts the BM environment using single-cell RNA sequencing analysis and to design pharmacological tools to efficiently mobilize BM stem and progenitor cells and Tregs into the blood circulation and islet-targeting nanoparticles loaded with chemokines to recruit these cells specifically into the islets to dampen the autoimmune response and elicit beta cell regeneration to treat T1D.
Cell differentiation, when a cell evolves from one state into a more specialized cell type, is a critical part of development. Dedifferentiation, when the process happens in reverse, of vascular smooth muscle cells (or synthetic VSMCs) is a known feature of vessel remodeling and dysfunction. Synthetic VSMCs can be found in multiple cardiovascular diseases (CVDs) including aneurysm, stroke, atherosclerosis, type 2 diabetes and vascular dementia.
Dr. Lino Cardenas’s investigations have led to the discovery of a novel pathologic epigenetic complex (HDAC9-MALAT1-BRG1) triggered by multiple vascular smooth muscle cell-related diseases. In addition, his research focus on the understanding of molecular mechanisms that affect the homeostasis of vascular tissue to the design of novel therapeutic interventions for the treatment of patients with CVDs.
Dr. Lino Cardenas’ Abstract
Aortic aneurysm is a common human condition, accounting for greater than 17,000 deaths annually in the United States. Aortic aneurysm places individuals at risk for aortic dissection (AoD), a life-threatening complication of aortic dilation, a malady with mortality rates measured at 1-2% per hour. During aortic aneurysm progression, vascular smooth muscle cells (VSMC) undergo dramatic changes in cellular phenotype.
Large scale rearrangements in cellular metabolism, impaired autophagy signaling, loss of cellular contractile elements and expansion of synthetic capacity. Our previous work has found that HDAC9 mediates the epigenetic downregulation of VSMC contractile genes via recruitment of the methyltransferase EZH2, the catalytic subunit of the PolyComb Repressive complex 2 (PRC2).
Interestingly, EZH2 is a negative regulator of autophagy activity with detrimental effects on VSMC survival. Autophagy is an evolutionarily conserved, tightly regulated process through which cells deliver unnecessary or potentially dangerous cellular materials in double-membrane vesicles for degradation via fusion with lysosomal compartments.
Our preliminary data indicates that in TAA models, HDAC9 binds to chromatin regions at autophagy-related gene-loci which associates with the accumulation of autophagy vesicle and cytotoxic materials (matrix proteases), indicating abnormal autophagy flux.
We expect this study will lead to an in-depth mechanistic understanding of the regulation and function of autophagy in normal vascular tissue and aneurysm disease and will provide insights into precise targeting of autophagy for aortic aneurysm treatment.
Dr. Dagogo-Jack’s research focuses on understanding mechanisms underlying response and resistance to novel targeted therapies in patients with cancer. She is investigating the role of non-invasive testing in molecular surveillance and detection of lung cancer, and developing clinical trials of novel drug combinations in lung cancer and mesothelioma.
Dr. Dagogo-Jack’s Abstract:
Lung cancers with anaplastic lymphoma kinase (ALK) rearrangements depend on ALK signaling and are initially markedly sensitive to ALK targeted therapies. However, the majority of these tumors will eventually develop refractoriness to ALK targeted therapy due to adaptations that promote dependence on other growth signals.
In current practice, “ALK-independent” growth signals are most often identified through direct analysis of biopsies obtained through invasive procedures or laboratory studies of cell lines derived from these biopsies. Through this grant, we will explore whether less invasive plasma analysis can identify genetic and proteomic alterations that are critical to survival of resistant ALK-positive lung cancers.
Furthermore, as we have shown that aberrant activation of the MET receptor contributes to 20% of relapses on ALK therapy and demonstrated that inhibiting both ALK and MET overcomes this type of resistance in preclinical models, we will conduct a clinical trial to evaluate the activity of the combination in patients with ALK-positive lung cancer with acquired MET signaling.
As there are no approved therapies for ALK-independent resistance and understanding of the molecular drivers of this important form of resistance is limited, these analyses have the potential to immediately impact patient care and inform future therapeutic strategies.
About the Mass General Research Institute
Research at Massachusetts General Hospital is interwoven through more than 30 different departments, centers and institutes. Our research includes fundamental, lab-based science; clinical trials to test new drugs, devices and diagnostic tools; and community and population-based research to improve health outcomes across populations and eliminate disparities in care.
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