This proposes a comprehensive 5-year physician scientist career development plan for Dr. Talia H. Swartz. Dr. Swartz completed a PhD in bacterial membrane bioenergetics, MD, and Residency in Internal Medicine and Fellowship in Infectious Diseases all at the Icahn School of Medicine at Mount Sinai. She has been exploring the role of purinergic signaling in HIV disease and has demonstrated that P2X receptors specifically are required for HIV viral membrane fusion. The application builds on Dr. Swartz's preliminary data supporting a key role for purinergic receptors in HIV entry and is structured to transition Dr. Swartz from trainee to independent investigator by leveraging intellectual and material resources at the Icahn School of Medicine at Mount Sinai. Dr. Benjamin Chen has mentored successful trainees and will guide Dr. Swartz throughout her training. Dr. Chen is an established investigator and recognized leader in HIV transmission. An advisory committee composed of highly regarded principal investigators in HIV research will provide additional guidance. Dr. Swartz's career development plan is comprehensive, including frequent meetings, specific relevant coursework, and departmental support centered on mentoring early career investigators. She will attend seminars and national conferences where she will continue to present her research, establish collaborations, and learn of recent advances in his field. Dr. Swartz's research utilizes state-of-the-art molecular and imaging methods to advance understanding of the role of purinergic signaling in HIV-1 infection. She proposes to study the mechanism of purinergic receptor signaling in HIV-1 infection. Purinergic receptors detect extracellular nucleotide that is released during inflammation. Dr. Swartz's preliminary experiments have demonstrated that P2X receptors are required for HIV-1 entry at the level of viral membrane fusion. In the first specific aim, experiments will be conducted to determine which of the three P2X receptors expressed on lymphocytes, P2X1, P2X4, and P2X7, is required for HIV entry using pharmacologic and genetic approaches.
The second aim will determine whether HIV can directly activate the receptor.
The third aim will address the role of purinergic signaling in inflammation using an ex vivo tonsil model that will build upon preliminary evidence that a P2X7 inhibitor reduces HIV productive infection. Inflammatory biomarkers will be tested to determine whether purinergic inhibition reduces levels of soluble pro-inflammatory cytokine production. Dr. Swartz has a successful research background with eight peer-reviewed publications, four of which are first author and a series of highly cited chapters. The preliminary data have been published in a manuscript this year and with results of a second manuscript with anticipated publication by the end of this year. The Icahn School of Medicine at Mount Sinai has demonstrated commitment to Dr. Swartz's career, with a 75% protected faculty position to conduct her research. Her goal is to develop a successful career as an independent physician scientist in defining key therapeutic agents in the treatment of HIV infection and inflammation.

Public Health Relevance

HIV is an important worldwide cause of morbidity and co-morbid conditions due to chronic inflammation despite effective anti-retroviral therapy. HIV infection requires purinergic receptors that mediate inflammatory signaling. This project aims to determine the mechanism by which purinergic signaling is required for HIV infection, its impact on chronic inflammation, and to develop novel therapeutic agents for HIV disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI120806-03
Application #
9418582
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Lawrence, Diane M
Project Start
2016-02-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Liu, Yuxin; Gaisa, Michael M; Wang, Xiaofei et al. (2017) Immune Microenvironments of Anal Cancer Precursors Differ by HIV-serostatus, Affecting Ablation Outcomes. J Infect Dis :
Esposito, Anthony M; Cheung, Pamela; Swartz, Talia H et al. (2016) A high throughput Cre-lox activated viral membrane fusion assay identifies pharmacological inhibitors of HIV entry. Virology 490:6-16