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  4. Sushil G. Rane, Ph.D.

Sushil G. Rane, Ph.D.

Updated photo of Sushil Rane
Scientific Focus Areas: Cell Biology, Developmental Biology, Genetics and Genomics, Molecular Biology and Biochemistry

Professional Experience

  • Senior Investigator, NIDDK, NIH, 2012–Present
  • Investigator, NIDDK, NIH, 2006–2012
  • NCI Scholar, NCI, NIH, 2001–2006
  • Fellow, Bristol-Myers Squibb Pharmaceutical Research Institute, 1997–1999
  • Ph.D., Temple University School of Medicine, 1996

Research Goal

The overarching research goal is to understand the growth and development processes of various organ systems tasked with maintaining glucose tolerance and energy homeostasis. Findings will provide an integrated view of the multi-organ communication that underlies normal glucose homeostasis, and its derangement in metabolic disease.

Current Research

Metabolic homeostasis is achieved via a concerted and integrative action of various organ systems, thus maintaining tight regulation of glucose levels. Dysfunction in one or more organ systems disturbs this homeostasis and propagates diabetes. Understanding the mechanisms that enforce glucose homeostasis and those that disrupt the tight regulation is thus of great medical significance. Our research over the past decade has been based on the central notion that the cell cycle network plays an integral role in maintenance of metabolic homeostasis and that mutations in cell cycle molecules contribute to metabolic dysfunction observed in diabetes and obesity. The abundance of cell cycle loci in genome-wide association studies of type 2 diabetes (T2D) lends credence to these hypotheses. We research two inter-related themes. First, we study the basic cellular processes that instruct development, growth and differentiation of metabolic organs. Second, we investigate the effects of mutations in key cell cycle molecules on the growth, development and function of these organs. Specifically, we are investigating the role of Cdks and the transforming growth factor-beta (TGF-ß) signaling pathway. Using tissue-specific conditional mouse models and primary cell culture-based systems, we aim to study the range of signals that determine growth, proliferation, differentiation, and apoptosis of cells that comprise the various metabolic tissues tasked with maintaining glucose homeostasis.

Applying our Research

Diabetes and obesity are global epidemics. Disease progression involves multi-organ dysfunction; thus, our findings will set the stage to help better our collective understanding of disease pathogenesis, with the potential to aid in the development of rational therapies.

Need for Further Study

The new information generated via genome-wide association studies of type 2 diabetes has offered many targets. These targets need to be validated by further experimentation. Moreover, type 2 diabetes pathogenesis cannot be fully explained by the findings of the genome-wide association studies, which is possibly due to small effects of multiple targets. An integrated molecular picture of multi-organ dysfunction will enable a better view into disease pathogenesis.

Select Publications

Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling.
Lee JH, Mellado-Gil JM, Bahn YJ, Pathy SM, Zhang YE, Rane SG.
Cell Death Dis (2020 Mar 13) 11:184. Abstract/Full Text
TGF-β receptor 1 regulates progenitors that promote browning of white fat.
Wankhade UD, Lee JH, Dagur PK, Yadav H, Shen M, Chen W, Kulkarni AB, McCoy JP, Finkel T, Cypess AM, Rane SG.
Mol Metab (2018 Oct) 16:160-171. Abstract/Full Text
View More Publications

Research in Plain Language

Our research group studies the molecular pathways that regulate glucose and energy balance in the body. These are critical areas of study related to the worldwide epidemic of obesity and diabetes. Specifically, we focus on the cell cycle – the process of cell division, replication, differentiation and death - that contributes to tissue development and renewal. We also study the growth factors involved in cellular signaling. Our group uses mouse models to study these processes. Specifically, we focus on signaling molecules, insulin-releasing beta cells, glucose regulation, and energy homeostasis.

Signaling molecules

Signaling molecules regulate the basic activity within cells. Transforming growth factor beta (TGF-beta) is a large family of signaling molecules. TGF-beta levels are elevated in diabetes and obesity. Using various methods, we study how this family of signaling molecules influences these diseases.

Our research demonstrated that TGF-beta triggers a signal that represses insulin. In our studies, we found that blocking this signal protects mice from obesity and diabetes. It also protected mice from developing the fatty liver that often accompany these conditions. Our findings suggest that modulating TGF-beta might treat these conditions.

Insulin-releasing beta cells

The cell cycle involves an enzyme called Cdk4. Our research shows that this enzyme regulates beta cell mass. The beta cell’s sensitivity to Cdk4 suggests potential diabetes therapies. Our group is investigating the molecular pathways that increase beta cell mass and function.

Glucose regulation and energy homeostasis

Glucose is the main sugar that passes through the gut and into the bloodstream. When an individual has blood glucose (blood sugar) levels that are above the normal range, they are at risk for or have diabetes. Homeostasis is the ability to maintain a constant internal environment in response to environmental changes.

We study how cell cycle regulators influence both glucose tolerance and homeostasis. We compare cell cycle molecules and biological pathways in obesity and diabetes. To do this, we use mouse models with mutations. Initial findings suggest that multiple cell cycle genes help modulate energy balance. We are testing the role of these molecules in regulating the growth, development and function of organs that regulate glucose levels.