Nikhil Dhurandhar - US grants

[unreadable] DESCRIPTION (provided by applicant): Obesity is a chronic condition with multiple causes, which has reached epidemic proportions in the U.S. The problem is compounded by a relative lack of effective treatments. Identifying and understanding various etiological factors involved may help in designing better treatments directed at the appropriate causes. Five viruses are reported to cause obesity in animal models, and viral infection may play an etiological role in some forms of human obesity. We recently reported adenovirus type-36 (Ad-36), the first human virus that increases adiposity in experimental animals including non-human primates and is associated with human obesity. Our in-vitro experiments with 3T3-L1 cells (rodent preadipocytes cell line) and human preadipocytes show Ad-36-induces up-regulation of fat cell differentiation and modulates the expression of several genes in fat cell differentiation pathway. Our central hypothesis is that up-regulation of fat cell differentiation contributes significantly to the adipogenic effect of Ad-36. The objective of this proposal is to identify the molecular interactions between fat cells and Ad-36, which will provide the basis to elucidate the mechanism of promotion of adipogenesis. Preliminary data suggested that the only a subset of viral genes are expressed in Ad-36 infected preadipocytes. In Specific Aim 1, we will begin by identifying the Ad-36 transcription units expressed during differentiation of infected preadipocytes. From these candidates, the Specific Aim 2 will identify the viral transcription unit(s) that enhance preadipocyte differentiation. Next, the Specific Aim 3 will determine the differentiation-associated changes in cellular gene expression prompted by the candidate transcription unit identified in Specific Aim 2 as well as Ad-36 virus. Ad-2, a non-adipogenic human adenovirus will be used as a negative control. Also, genes found to enhance the differentiation of 3T3-L1 cells will be tested for their effect on differentiation of human preadipocytes. Identifying the interacting viral and cellular genes will help in future for elucidating novel signaling controls of fat cell differentiation and molecular pathway(s) for Ad-36 induced adiposity. Such an understanding of the mechanism of Ad-36 induced adiposity will help in determining the contribution of Ad-36 infections in human obesity. We believe that determining the role of viral infections in human obesity may influence the treatment, management, and possible prevention of such type of obesity. [unreadable] [unreadable]

The emergence of COVID-19, the disease caused by CoV-2 (coronavirus-2), has created a large global outbreak and an unprecedented health crisis. Without effective vaccines or therapies, there is an urgent need for strategies for prevention or treatment of CoV-2 infection and for minimizing, when possible, the effects of health related issues that make a person more likely to have severe symptoms and complications. One high risk group are those with type 2 diabetes (TB2 = adult onset diabetes) and obesity (approximately 85% of people with TB2) who are taking anti-diabetes drugs that may be increasing their COVID-19 susceptibility by stimulating the receptors (ACE2) on the surfaces of adipose/fat cells that allow CoV-2 entry. Some, but not all, anti-diabetes drugs increase ACE2 expression, and the effect of all anti-diabetes drugs on ACE2 expression is unknown. Thus, the goal of this project is to use computer simulations and experiments to determine the effect of key anti-diabetic agents on ACE2 expression and to test the hypothesis that the anti-diabetes drugs that increase ACE2 expression facilitate CoV-2 entry. While the obesity status of COVID-19 infected individuals cannot be changed rapidly, their diabetes medication can rapidly be switched to a safer option, which may save many lives. This project will also provide an outstanding interdisciplinary training/learning opportunity for a graduate student from Chemical Engineering department and for a post-doctoral fellow from Nutritional Sciences, and the investigators? access to patients with obesity and diabetes and health care providers will enable a portal for societal outreach to disseminate relevant findings of this study in the West Texas region.

The goal of this project is to determine the effect of key anti-diabetic agents on the expression of ACE2 (Angiotensin Converting Enzyme 2) receptors, which control the entry of C0V-2 (the virus responsible COVID-19) into adipose cells and to test the hypothesis that anti-diabetes drugs that increase ACE2 expression facilitate CoV-2 infection. The project is motivated by several key observations: 1) that COVID-19-related mortality is greater in people with obesity and type 2 diabetes (T2D); 2) that ACE2 is present in adipocytes as well as lung alveolar epithelial cells (the preferred target of CoV-2); 3) that overexpression of ACE2 can facilitate CoV-2 entry and subsequent severity of infection; and 4) that some, but not all, anti-diabetes drugs increase ACE2 expression. The Research Plan is organized under two aims. The FIRST Aim is to use molecular modeling to test the efficacy of CoV-2 infection in the presence of anti-diabetic agents. The base model system for these simulations consists of the Spike protein located on the surface of CoV-2 and the ACE2 cell surface receptor to which it binds to enable viral entry. Models will be developed to compare the energetics and the mechanism and to characterize the rate of CoV-2-spike protein to ACE2 receptor binding in the presence of different anti-diabetic drugs. Of particular interest are those drugs known to upregulate ACE2, e.g., pioglitazone, SGLT-inhibitor, and liraglutide. The SECOND Aim is to test cellular validation of molecular modeling in the presence of anti-diabetic agents. The drug targets identified by molecular modeling in Aim 1 will be validated using human adipose-derived stromal/stem cells (hASC) and human lung epithelial cells (A549 line) as a positive control. Studies are designed to identify anti-diabetic drugs that do or do not promote CoV-2 infection in cells and to test the anti-diabetic efficacy of the drugs that do not promote CoV-2 infection. Results obtained from this project are expected to provide new insights into how certain anti-diabetic drugs increase the expression of ACE2 receptor and promote cellular entry of CoV-2 virus as well as identify anti-diabetic drugs that do not promote CoV-2 entry into the cells and maintain their anti-diabetic efficacy despite the presence of the virus.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.