Physicians

Department / Division
Pediatrics / Pediatrics-Endocrinology

Address
DUMC 102820
Durham, NC 27710

Appointment Telephone
919-684-3772, option 2

Office Telephone
919-684-8292

Fax Telephone
919-684-8613

Training

• MD, Mayo Medical School (Minnesota), 2003

Residency

• Pediatrics, Duke University Medical Center, 2003-2006

Fellowship

• Pediatric Endocrinology, Duke University Medical Center, 2006-2009

Other Training

• PhD, Immunology, Mayo Graduate School (Minnesota), 2003

Clinical Interests
Short stature, puberty, polycystic ovarian syndrome, thyroid disease

Research Interests
Nutritional status is critically important for normal immune function in individuals. While malnutrition reduces immune function and increases markedly the risks and mortality from severe infections, obesity heightens immune reactivity and predisposes to systemic inflammation that fosters the development of inflammatory disorders including autoimmunity, type 2 diabetes, coronary artery and renovascular diseases. Studies during the last decade implicate a novel mechanism by which malnutrition causes immune dysfunction: a deficit of the adipocyte hormone leptin, resulting from generalized wasting and depletion of stores of adipose tissue. Leptin has now been shown to be a critical regulator of immune cell number and function. Leptin deficiency results in altered immune responses, affecting both innate and adaptive immunity. Leptin is particularly important for T cells, as leptin-deficient individuals have decreased T cell number, decreased CD4+ T helper cells, and abnormal T cell function, resulting in increased susceptibility to intracellular infections. And while the pathogenesis of obesity-related inflammation is incompletely understood, there is evidence that heightened production of leptin and other inflammatory adipocytokines play a central role. There is, therefore, a critical need to clarify the mechanisms by which leptin and other adipocytokines communicate nutritional status to influence immune cell metabolism and function.

As key players in the adaptive immune response, lymphocyte (T and B cell) survival and function must be tightly controlled to maintain proper immunity while preventing inappropriate inflammatory immune responses or immune-deficiency. We have found that T cell glucose uptake and metabolism are highly regulated and can exert strong effects on T cell differentiation and function, and that leptin is required for normal T cell glucose uptake and metabolism in activated cells.

Our long-term goal is to investigate the interactions between adipocytes and immune cells, specifically lymphocytes, in order to better understand the causes of immune dysregulation in both obesity and malnutrition. Our current studies include the following:

1. Identify the signals required to allow peripheral T cells to become sensitive to leptin.
2. Test the hypothesis that leptin has a cell intrinsic role in peripheral T cell metabolism and function in vivo.
3. Explore the molecular mechanisms by which leptin alters T cell metabolism, function and immunity.
4. Understand the role of AMP kinase (AMPK) activation as an important mediator of glucose metabolism following leptin stimulation in T cells.
5. Understand how nutritional changes alter T cell function and immunity and disrupt T cell homeostasis.
6. Understand how leptin levels influence T cell function both during and after acute malnutrition and affect morbidity and mortality from viral infection in malnourished animals.

Industry Relationships and Collaborations (What's this?)

This faculty member has no reported relationships with industry.

Representative Publications
MacIver, NJ; Blagih, J; Saucillo, DC; Tonelli, L; Griss, T; Rathmell, JC; Jones, RG. The liver kinase B1 is a central regulator of T cell development, activation, and metabolism. Journal of Immunology. 2011;187:4187-4198. (2011) Abstract

Michalek, RD; Gerriets, VA; Jacobs, SR; Macintyre, AN; MacIver, NJ; Mason, EF; Sullivan, SA; Nichols, AG; Rathmell, JC. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. Journal of Immunology. 2011;186:3299-3303. (2011) Abstract

Jacobs, SR; Herman, CE; Maciver, NJ; Wofford, JA; Wieman, HL; Hammen, JJ; Rathmell, JC. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. Journal of Immunology. 2008;180:4476-4486. (2008) Abstract

Maciver, NJ; Jacobs, SR; Wieman, HL; Wofford, JA; Coloff, JL; Rathmell, JC. Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. Journal of Leukocyte Biology. 2008;84:949-957. (2008) Abstract

Solan, NJ; Miyoshi, H; Carmona, EM; Bren, GD; Paya, CV. RelB cellular regulation and transcriptional activity are regulated by p100. Journal of Biological Chemistry. 2002;277:1405-1418. (2002) Abstract

Asin, S; Bren, GD; Carmona, EM; Solan, NJ; Paya, CV. NF-kappaB cis-acting motifs of the human immunodeficiency virus (HIV) long terminal repeat regulate HIV transcription in human macrophages. Journal of Virology. 2001;75:11408-11416. (2001) Abstract

Bren, GD; Solan, NJ; Miyoshi, H; Pennington, KN; Pobst, LJ; Paya, CV. Transcription of the RelB gene is regulated by NF-kappaB. Oncogene. 2001;20:7722-7733. (2001) Abstract

Solan, NJ; Ward, PE; Sanders, SP; Towns, MC; Bathon, JM. Soluble recombinant neutral endopeptidase (CD10) as a potential antiinflammatory agent. Inflammation. 1998;22:107-121. (1998) Abstract