Funding opportunities

Molecular Determinants of Human Brown Fat Lineage Specification and Reprogramming

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-05997
Funds requested: 
$1 254 130
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Brown fat, once thought to be present in humans only during the neonatal period, has now definitively been shown to be present throughout human life. As opposed to white fat (that stores energy), brown fat burns energy and increasing the levels of brown fat has the potential to dramatically improve energy metabolism in humans. The proposed research focuses on: 1) revealing the molecular mechanism of a new factor we identified that determines if a cell will become a brown fat cell (identity) and 2) if stem cell biology can be used to generate patient specific brown fat as a therapeutic strategy for people with metabolic diseases such as obesity and diabetes. In particular, we will test if the brown fat that we can generate from patients' skin cells using stem cell biology, is competent to improve metabolism in an animal. We will also compare engineered brown fat to endogenously formed human fat at molecular and functional levels to test how faithful our system is to bona fide brown fat. Finally, we will elucidate the molecular mechanism by which our factor directs brown fat identity. Our vision is that these initial basic stem cell biology studies will make it possible to overcome the current hurdle to develop potent and effective therapies for patients with life-threatening complications from metabolic diseases.
Statement of Benefit to California: 
According to the Center for Disease Control, over 24% of Californians (greater than 9 million people in this state alone) are obese and this rate continues to rise every year. The reason for the dramatic increase over the past decades is not fully understood but seems to be multifactorial including changes in: lifestyle, environment and epigenetics. As obesity is directly linked to a number of diseases such as diabetes, dyslipidemia and hypertension, the impact of this problem in terms of morbidity and mortality for Californians has been devastating. In spite of an enormous effort from a number of approaches, ranging from changes in public policy to medical interventions, the incidence of obesity and the associated diseases continues to escalate. This dismal success rate underscores the urgent need for new ideas and approaches to address this major public health problem. The proposed study seeks to capitalize on the potential of stem cell biology to offer new alternative therapies for these devastating diseases. If successful, our studies will lay the foundation for a new paradigm opening up the possibility to regenerate a healthy energy balance in patients suffering from the consequences metabolic diseases. In addition to the health benefits for citizens, developing this new technology and potential therapy in California could contribute to the state's important biotechnology industry.
Review Summary: 
The applicant proposes to explore the mechanisms by which cells acquire a brown fat rather than a white fat fate and test the potential of brown fat cells to improve energy metabolism. The investigators have shown that a specific gene regulates the formation of brown fat in vitro, and they plan to determine whether human cells lacking this gene’s function are converted to bona fide brown fat cells by testing their impact upon metabolism in mice in vivo. The investigators next propose to use two methods to confirm the role of the gene in brown fat formation. They will exploit human induced pluripotent stem cell (hiPSC) technology to generate brown fat from patients with and without mutations in the gene. They will also manipulate the gene in normal cells and generate brown fat. The resultant fat cells will be compared to human brown fat samples and tested for function in vivo as above. In the last series of studies, investigators will use a mouse model to explore the molecular mechanism by which the gene regulates brown fat fate. Significance and Innovation - Reviewers appreciated the gravity of the burden presented by metabolic diseases such as obesity and diabetes, and were intrigued by the potential to treat obesity by replacing white fat with brown fat. - While the work could contribute to the understanding of metabolic disease, the panel questioned the relevance of stem cells to the work and its significance to stem cell biology. Feasibility and Experimental Design - The stem cell biology presented in the application was weak. For example, the application fails to present a compelling rationale for the use of hiPSC rather than primary cells, and refers to well-documented normal differentiation processes as “direct reprogramming”. - The application lacks preliminary data supporting the team’s ability to generate fat cells from hiPSC and the proposed method appears inappropriate when starting with this cell type. - Reviewers were enthusiastic about the novel finding that manipulating the function of the gene under investigation could direct human cells toward brown fat rather than white fat formation. Principal Investigator (PI) and Research Team - The PI is well trained; however, his/her limited experience and track record in human stem cells, particularly hiPSC, lowers the program’s chance of success. - The concern above was further amplified by the minimal commitment of the collaborator and postdoctoral fellow intended to provide stem cell expertise. Responsiveness to the RFA - This proposal is poorly responsive to the RFA. Stem cells are not necessary for the bulk of the work, and one aim appears completely out of scope and uses no stem cells at all.
Conflicts: 
  • James Ellis

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